TW202304973A - 用以篩選對間皮素具有專一性之抗體片段的噬菌體表現單鏈變異片段抗體庫 - Google Patents
用以篩選對間皮素具有專一性之抗體片段的噬菌體表現單鏈變異片段抗體庫 Download PDFInfo
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Abstract
本揭示內容是關於一種由噬菌體表現之單鏈變異片段(single-chain variable fragment, scFv)抗體庫,包含複數個由噬菌體表現的scFv,其特徵在於CDR具有特定序列。本揭示內容之由噬菌體表現的scFv抗體庫可用以篩選對間皮素(mesothelin, MSLN)具有結合親和力及專一性的抗體片段。本揭示內容亦提供一種對MSLN具有專一性的重組抗體、一種包含該重組抗體的免疫偶聯物,以及其用以治療癌症的用途。
Description
本揭示內容係關於包含不同抗體片段之抗體庫的領域。具體來說,本揭示內容係關於一種由噬菌體表現的單鏈變異片段(single-chain variable fragment, scFv)抗體庫,以及其於篩選治療癌症(特別是具有間皮素(mesothelin, MSLN)表現之癌症)之抗體片段的用途。
標的MSLN是一種具有潛力的癌症治療策略,已有許多臨床試驗將其應用以治療多種癌症。目前已知有多種惡性腫瘤細胞會過量表現MSLN。就分子層面來說,已知癌症抗原125 (cancer antigen 125, CA-125;亦稱為黏液素16 (Mucin 16, MUC16))參與調控的細胞與細胞交互作用會導致腫瘤的生成及擴增,而MSLN則會與CA125反應進而增加胰臟癌細胞的移動及侵略性。過量表現MSLN會活化核因子活化B細胞κ輕鏈增強子(nuclear factor kappa-light-chain-enhancer of activated B cell, NF-κB)、有絲分裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK),以及磷酸肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)等路徑,使胰臟癌細胞對細胞凋亡產生耐受性。此外,過量表現MSLN亦會活化與胰臟癌細胞侵襲相關之MMP-7,並導致惡性胸膜間皮細胞瘤中MMP-9的表現量增高,而促使腫瘤的侵襲反應。臨床數據指出,MSLN表現量的增加會造成多種癌症病患之腫瘤體積增加,且降低整體存活率;基於MSLN的正常表現僅侷限於間皮細胞,而此表現並非絕對必要且不具實質性的副作用,MSLN因此可作標靶治療的候選蛋白,以治療不同癌症。
相關研究已證實標的MSLN的抗體-藥物偶聯物(antibody-drug conjugate, ADC)可用以治療會表現MSLN之癌症。然而,開發作為ADC之標的模組(targeting module)的抗體,據以將毒性藥物傳送至腫瘤處而不會影響正常組織,仍存在著許多潛在的障礙。基本上,成功的ADC開發至少需滿足以下標準:(1) 製備足夠產量之ADC的可行性;(2) ADC對標的抗原具有適當的結合親和力及專一性;(3) ADC與抗原決定區上的抗原結合,其中該抗原在生物學相關狀態下可與ADC結合;(4) ADC與適當的抗原決定位結合後可被內化至細胞中;(5) 藉由受器媒介之胞吞反應進入細胞後,ADC-抗原複合體可釋放出毒性藥物。實務上,候選抗體要同時滿足以上標準並不容易達成。
有鑑於此,本發明相關領域亟需一種可有效製備對MSLN具有足夠專一性及/或親和力之抗體的方法,據以研發可用以治療癌症(特別是具有MSLN表現之癌症)的ADC。
發明內容旨在提供本揭示內容的簡化摘要,以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述,且其用意並非在指出本發明實施例的重要/關鍵元件或界定本發明的範圍。其唯一目的是以簡化的概念形式呈現本揭示內容的一些概念,以作為呈現於後文中更詳細描述的序言。
本揭示內容的第一態樣是關於一種由噬菌體表現的scFv抗體庫,其包含複數個由噬菌體表現的scFv。在結構上,各由噬菌體表現的scFv包含一第一輕鏈互補決定區(first light chain complementarity determining region, CDR-L1)、一第二輕鏈互補決定區(second light chain CDR, CDR-L2)、一第三輕鏈互補決定區(third light chain CDR, CDR-L3)、一第一重鏈互補決定區(first heavy chain CDR, CDR-H1)、一第二重鏈互補決定區(second heavy chain CDR, CDR-H2)以及一第三重鏈互補決定區(third heavy chain CDR, CDR-H3)。依據本揭示內容實施方式,該CDR-L1是由一包含序列編號:1之核苷酸序列的第一編碼序列所編碼而成;該CDR-L2是由一包含序列編號:2之核苷酸序列的第二編碼序列所編碼而成;該CDR-L3是由一包含序列編號:3之核苷酸序列的第三編碼序列所編碼而成;該CDR-H1是由一包含序列編號:4之核苷酸序列的第四編碼序列所編碼而成;該CDR-H2是由一包含序列編號:5之核苷酸序列的第五編碼序列所編碼而成;且該CDR-H3是由一包含序列編號:6之核苷酸序列的第六編碼序列所編碼而成。
依據某些實施方式,本揭示內容由噬菌體表現之scFv抗體庫的噬菌體為M13噬菌體或T7噬菌體。在某些操作性實施例中,該噬菌體為M13噬菌體。
依據某些實施方式,由噬菌體表現scFv抗體庫包含第一、第二、第三以及第四由噬菌體表現之scFv,其中該第一由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2以及CDR-H3包含序列編號:7、8、9、10、11及12的胺基酸序列;該第二由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2以及CDR-H3包含序列編號:13、14、15、16、17及12的胺基酸序列;該第三由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2以及CDR-H3包含序列編號:7、18、19、20、21及22的胺基酸序列;以及該第四由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2以及CDR-H3包含序列編號:23、24、25、26、27及12的胺基酸序列。
依據本揭示內容某些實施方式,本發明scFv抗體庫中至少一個由噬菌體表現之scFv對MSLN具有專一性。
本揭示內容的第二態樣係關於一種對MSLN具有專一性的重組抗體。依據某些實施方式,該重組抗體是源自本發明由噬菌體表現的scFv抗體庫,其在結構上包含一輕鏈變異(light chain variable, VL)域以及一重鏈變異(heavy chain variable, VH)域,其中該VL域含一CDR-L1、一CDR-L2及一CDR-L3;且該VH域包含一CDR-H1、一CDR-H2及一CDR-H3。
依據某些實施方式,CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:7-12的胺基酸序列。依據某些較佳的實施方式,該VL域包含一與序列編號:28具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:29具有至少85%之序列相似度的胺基酸序列。在某些操作性實施例中,該VL域及VH域分別包含與序列編號:28及29具有100%之序列相似度的胺基酸序列。
依據某些實施方式,該CDR-L1、CDR-L2及CDR-L3分別包含序列編號:13-15的胺基酸序列,且該CDR-H1、CDR-H2及CDR-H3分別包含序列編號:16、17及12的胺基酸序列。依據某些較佳的實施方式,該VL域包含一與序列編號:30具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:31具有至少85%之序列相似度的胺基酸序列。在某些操作性實施例中,該VL域及VH域分別包含與序列編號:30及31具有100%之序列相似度的胺基酸序列。
依據可選擇的實施方式,該CDR-L1、CDR-L2及CDR-L3分別包含序列編號:7、18及19的胺基酸序列,且該CDR-H1、CDR-H2及CDR-H3分別包含序列編號:20-22的胺基酸序列。依據某些較佳的實施方式,該VL域包含一與序列編號:32具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:33具有至少85%之序列相似度的胺基酸序列。在某些操作性實施例中,該VL域及VH域分別包含與序列編號:32及33具有100%之序列相似度的胺基酸序列。
依據某些實施方式,該CDR-L1、CDR-L2及CDR-L3分別包含序列編號:23-25的胺基酸序列,且該CDR-H1、CDR-H2及CDR-H3分別包含序列編號:26、27及12的胺基酸序列。依據某些較佳的實施方式,該VL域包含一與序列編號:34具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:35具有至少85%之序列相似度的胺基酸序列。在某些操作性實施例中,該VL域及VH域分別包含與序列編號:34及35具有100%之序列相似度的胺基酸序列。
依據所欲目的,該重組抗體的形式可以是一完整的抗體(例如,一免疫球蛋白)或是一包含VL域及VH域的抗體片段(例如,一scFv或一抗原結合區(fragment antigen-binding, Fab))。
所述重組抗體適用於製備一用以治療癌症(例如,MSLN-陽型的癌症)的ADC。據此,本揭示內容的第三態樣係關於一種標的MSLN的免疫偶聯物(immunoconjugate)。該偶聯物在結構上包含一本發明重組抗體、一功能性模體(functional motif)以及一連接該重組抗體及該功能性模體的連接子(linker)。
依據某些實施方式,所述功能性模體包含一免疫毒素,舉例來說,一外毒素(例如,綠膿桿菌外毒素(
Pseudomonas Exotoxin, PE) A或其衍生物)。在某些例示性實施方式中,該外毒素是一截斷的PE A次單元毒素。非必要的,該功能性模組更包含一與免疫毒素連接的內質網(endoplasmic reticulum, ER)滯留胜肽(retention peptide)。依據某些操作性實施例,該ER滯留胜肽包含「KDEL」(序列編號:36)的胺基酸序列,且是位於PE A次單元毒素的C-端。
依據可選擇的實施方式,功能性模體包含一細胞毒性劑,例如,澳瑞他汀(auristatin)或其衍生物。在一操作性實施例中,該細胞毒性劑為單甲基澳瑞他汀E (monomethyl auristatin E, MMAE)。
本發明免疫偶聯物的該連接子可以是,(1)纈胺酸-瓜胺酸雙胜肽;(2)包含序列編號:37之胺基酸序列的第一多肽;或者(3)一適體(adaptor),包含至少一AL模組,其中該AL模組包含一位於N-端的蛋白A片段,一位於C-端的蛋白L片段,以及一連接該蛋白A片段及該蛋白L片段的第二多肽。依據一特定實施例,該適體包含序列編號:38的胺基酸序列。
本揭示內容的另一態樣是關於一種藥學組合物,其包含一本揭示內容任一實施方式所述的免疫偶聯物,以及一藥學上可接受之載體。
本揭示內容一提供一種用以治療一個體之癌症的方法。該方法包含對該個體投予一有效量的免疫偶聯物或本揭示內容任一態樣及實施方式的藥學組合物。依據某些實施方式,該癌症會表現MSLN,亦即MSLN-陽性的癌症。
適用以本發明方法治療的癌症包含胃癌、肺癌、膀胱癌、乳癌、胰臟癌、腎癌、大腸直腸癌、子宮頸癌、卵巢癌、腦瘤、前列腺癌、肝細胞癌、黑色素瘤、食道癌、多發性骨髓瘤或是頭頸部鱗狀細胞癌。依據一實施方式,該癌症為胃癌。依據另一實施方式,該癌症為胰臟癌。
該個體為一哺乳類;較佳地,該個體為人類。
在參閱以下的詳細說明及隨附圖式後,本揭示內容諸多伴隨的特徵及優點當可輕易瞭解。
為了使本揭示內容的敘述更加詳盡與完備,下文針對了本發明的實施態樣與具體實施例提出了說明性的描述;但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而,亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
I. 定義
為方便起見,本說明書、實施例及所附申請專利範圍中所使用的特定專有名詞集中於此。除非本說明書另有定義,否則此處所使用的科學及技術詞彙的含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。並且,在不和上下文衝突的情形下,本說明書所用的單數名詞涵蓋該名詞的複數型;而所用的複數名詞時亦涵蓋該名詞的單數型。具體來說,在本說明書與申請專利範圍中,單數形式「一」(a及an)包括複數參考值,但依據上下文而有明確表示者除外。此外,本說明書與申請專利範圍中,「至少一」(at least one)與「一或多」(one or more)表述方式的意義相同,兩者都代表包含一、二、三或更多。
雖然用以界定本發明較廣範圍的數值範圍及參數皆是約略的數值,此處已盡可能精準地呈現具體實施例中的相關數值。然而,任何數值本質上不可避免地含有因個別測試方法所導致的標準偏差。並且,在此處,「約」(about)一詞通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是,「約」一詞代表實際數值落在平均值的可接受標準誤差之內,視本發明所屬技術領域中具有通常知識者的考量而定。除了實施例之外,或除非另有明確地說明,當可理解此處所用的所有範圍、數量、數值以及百分比(例如,用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他類似者)均經過「約」的修飾。據此,除非另有相反的說明,本說明書與申請專利範圍所揭示的數值參數皆為約略的數值,可視需求而更動。至少,應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。
「抗體」(antibody)一詞在本揭示內容中具有最廣泛的意義,具體來說包含單株抗體(包括全長的單株抗體)、多株抗體、多功(multi-specific)或多效(multivalent)抗體(例如,雙功(bi-specific)抗體)以及具有欲求之生物活性的抗體片段。「抗體片段」(antibody fragment或the fragment of an antibody)一詞是指全長抗體的一部分,一般為一全長抗體的抗原結合域或變異域(即VL域及VH域)。例示性的抗體片段包含抗原結合片段(fragment antigen-binding, Fab)、Fab’、F(ab’)2、單鏈變異片段(single-chain variable fragment, scFv)、雙鏈抗體(diabody)、線性抗體(linear antibody)、單鏈抗體分子,以及由抗體片段所形成的多功抗體。
在本揭示內容中,「抗體庫」一詞是指抗體集/或表現以篩選及/或組合成一完整抗體的抗體片段的集合。該抗體及/或抗體片段可表現於一核糖體、一噬菌體或一細胞表面,特別是一酵母菌的細胞表面。
「單鏈變異片段」(single-chain variable fragment, scFv)一詞是指包含一免疫球蛋白的重鏈變異域(variable domain of the heavy chain)及輕鏈變異域(variable domain of the light chain)的重組蛋白,其中該VH域及VL域是以共價鍵結形成VH::VL異二聚體。該VH及VL可直接連結或是透過一由胜肽編碼之連接子(linker)連結,其中該連接子可連接VH的N-端及VL的C-端,或者是連接VH的C-端及VL的N-端。連接子通常為包含多個能增加可撓性之甘胺酸(glycine)及多個能增加溶解性之絲胺酸(serine)或蘇胺酸(threonine)。即使移除抗體之恒定域且插入連接子,scFv蛋白仍保有原免疫球蛋白的專一性。可由包含用以編碼VH及VL序列的核酸來表現scFv多肽抗體。
「互補決定區」(complementarity determining region, CDR)一詞是指抗體分子的高變區(hypervariable region),其形成一個與所結合之抗原的3維表面互補的表面。從N-端到C-端,各抗體的重鏈和輕鏈包含三個CDR (即CDR-1、CDR-2和CDR-3)。因此,一人類白血球抗原-DR (human leukocyte antigen-DR, HLA-DR)的結合位點總共包括六個CDR,其中包含三個來自重鏈變異域的CDR (即CDR-H1、CDR-H2和CDR-H3),以及三個來自輕鏈變異域的CDR (即CDR-L1、CDR-L2和CDR-L3)。CDR的胺基酸殘基與所結合的抗原緊密接觸,其中與抗原最密切接觸的通常是重鏈CDR3。
本文所使用之抗體的「變異區」(variable region)一詞是指抗體重鏈或輕鏈的胺基末端區域。該些區域通常是一抗體中最具變異性的部份,包含抗原結合位點。「變異的」(variable)一詞是指該變異區的某些部分在不同抗體之間在序列上有很大差異的事實,其係用於決定每個特定抗體對其特定抗原的結合和專一性。然而,該變異性(variability)並非均勻分布於抗體的變異區內。它是集中在輕鏈及重鏈的互補決定區或高變區的三個區段中。變異區中具有高度保守的部分稱為框架(framework, FR)。天然重鏈及輕鏈的變異區包含4個FR區,其主要採用β-折板(β-sheet)的配置,並由三個CDR連接,該三個CDR形成連接β-折板結構的環,在某些情況下會形成β-折板結構的一部分。各個鏈中的CDR由FR區緊密連接在一起,並且與來自另一條鏈的CDR一起形成抗體的抗原結合位點。恆定區不直接參與抗體與抗原的結合,但表現出各種效應子(effector)的功能,例如參與在抗體的抗體依賴性細胞毒性(antibody-dependent cellular toxicity)效應中。
「序列相似度百分比(%)」(percentage (%) sequence identity)在本揭示內容所揭示的任一種胺基酸序列中是定義為候選序列中的胺基酸殘基與特定參考序列中的胺基酸殘基相同的百分比,在比對序列時可視需要來引入間隙(gap),藉以達到最大的序列相似度百分比,並且不考慮任何保守性置換(conservative substitution)作為序列相似度的一部分。可利用各種本領域技術人員所熟知的方法來進行比對,以確認序列相似度百分比,舉例來說,可利用例如BLAST、BLAST-2、ALIGN或Megalign (DNASTAR)等公開的電腦軟體來進行比對。本技術領域相關人士可以決定測量比對的適當參數,包含任一種所需的運算法以利使所比對的全長序列達到最大比對值。爲達本文的目的,兩個胺基酸序列之間的序列比對是利用國家生物技術資訊中心(Nation Center for Biotechnology Information,NCBI)提供的電腦程式Blastp (protein-protein BLAST)來分析。一特定序列A及一特定序列B之間的序列相似度百分比(亦可表述為一特定序列A與一特定序列B具有某特定百分比的序列相似度)是利用下列公式來計算:
其中X是經序列比對程式BLAST後,在該程式中的A和B比對中被評定為相同匹配的胺基酸殘基數量(identical matches),Y則是特定序列B中的胺基酸殘基總數。
如在本文中所討論的,抗體的胺基酸序列中具有些微變化亦視為涵蓋在本揭示內容和請求保護的發明構思中,只要該胺基酸序列的變異度保持至少85%的序列相似度,例如至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%和99%的序列相似度。本揭示內容的抗體可進行特定修飾,來改變與其生理活性無關的該胜肽的特徵。舉例來說,可以改變及/或剔除某些胺基酸,而不影響本發明抗體的生理活性(亦即與IAV或IBV結合的能力)。特別是,保守性胺基酸發生置換是可以預期的。保守性置換(conservative replacement)是指在其側鏈具有相關性的胺基酸家族中所發生的置換。一般來說,由基因編碼的胺基酸可分為四大類:(1)酸性胺基酸,即天門冬胺酸(aspartate)、麩胺酸(glutamate);(2)鹼性胺基酸,即離胺酸(lysine)、精胺酸(arginine)、組胺酸(histidine);(3)非極性胺基酸,即丙胺酸(alanine)、纈胺酸(valine)、白胺酸(leucine)、異白胺酸(isoleucine)、脯胺酸(proline)、苯丙胺酸(phenylalanine)、甲硫胺酸(methionine)、色胺酸(tryptophan);以及(4)非帶電極性胺基酸,即甘胺酸(glycine)、天門冬醯胺(asparagine)、麩醯胺酸(glutamine)、半胱胺酸(cysteine)、絲胺酸(serine)、蘇胺酸(threonine)、酪胺酸(tyrosine)。較佳的分類是:絲胺酸及蘇胺酸係屬脂肪羥基(aliphatic-hydroxy)類;天冬醯胺酸及麩醯胺係屬含醯胺(amide-containing)類;丙胺酸、纈胺酸、白胺酸及異白胺酸係屬脂肪類;而苯丙胺酸、色胺酸及酪胺酸則屬芳香(aromatic)類。舉例來說,可以合理預期將白胺酸單獨置換成異白胺酸或纈胺酸,將天門冬胺酸置換成麩胺酸,將蘇胺酸置換成絲胺酸,或是將一胺基酸進行類似的置換並換成一結構相關的胺基酸而不會對所得分子的結合或特性產生重大影響,特別是當該置換並未涉及框架位點內的胺基酸時。藉由測定胜肽衍生物的比活性(specific activity),可以很容易地確認胺基酸變化是否會產生功能性胜肽。本領域具有通常知識者可以容易地製備抗體的片段或類似物。較佳的片段或類似物的胺基末端和羧基末端會出現在功能性區域的邊界附近。
「噬質體」(phagemid)一詞是指一結合噬菌體及質體特性的載體。細菌噬菌體是是指任何一種可感染細菌的病毒。
「核苷酸序列」(nucleic acid sequence)、「核苷酸序列」(nucleotide sequence)或「核酸」(nucleic acid) 在本說明書中為可互換的詞彙,依據本揭示內容,當可理解該些詞彙是指一雙股去氧核糖核酸(deoxyribonucleic acid, DNA、一單股DNA或該DNA的轉錄產物(例如核糖核酸(ribonucleic acid, RNA)分子)。應可理解本揭示內容不涉及存在於其自然環境及狀態下的基因體多核苷酸序列。本發明之核酸、多核苷酸或核苷酸序列可以分離方法或基因工程方法(genetic engineering method)進行萃取及純化(或部分純化);該分離方法包含,但不限於,離子交換層析法(ion-exchange chromatography)及分子粒徑篩析層析法(molecular size exclusion chromatography);基因工程方法則可以是放大(amplification)、扣除雜交法(subtractive hybridization)、轉殖(cloning)、次轉殖(sub-cloning)、化學合成或該些基因工程方法之組合。
本揭示內容中「編碼序列」(coding sequence)是指核苷酸序列及核苷酸序列,包含RNA及DNA兩者,其可編碼用以合成RNA、蛋白質、部份RNA或部分蛋白質所需的基因訊息。一生物體基因體之自然產物以外的核苷酸序列稱為「外來核苷酸序列」(foreign nucleotide sequence)、「異源性核苷酸序列」(heterologous nucleotide sequences)或「外源性核苷酸序列」(exogenous nucleotide sequences)。「異源性蛋白」(heterologous proteins)是指由外來、異源性或外源性核苷酸編碼之蛋白,因此在細胞中通常不會天然表現這些蛋白。經分離後重新引入相同種類(例如,同一物種)之生物體的核苷酸序列不屬於該特定生物體基因組天然產生的產物,而會視為異性或外源性核苷酸序列。
「個體」(subject)一詞是指一包含人類在內可適用本揭示內容抗體、免疫偶聯物、藥學組合物及/或方法治療的哺乳類。除非另有所指,否則「個體」一詞同時意指雄性及雌性。
II. 發明說明
本揭示內容旨在提供一種用以研發抗體之由噬菌體表現的scFv抗體庫,其中該抗體對腫瘤相關抗原(tumor-associated antigen, TAA) (例如,MSLN)具有結合親和力及/或專一性,因此可與一治療劑偶聯以標的及治療癌症(例如,具有MSLN表現的癌症)。
(II-1)
噬菌體表現之
scFv
抗體庫
本揭示內容的第一態樣係關於一種由噬菌體表現之scFv抗體庫,其包含複數個由噬菌體表現之scFv。在結構上,各scFv皆包含三個位於重鏈的CDR (亦即CDR-H1、CDR-H2和CDR-H3),以及三個位於輕鏈的CDR (亦即CDR-L1、CDR-L2和CDR-L3)。依據本揭示內容某些實施方式,該CDR-L1是由一包含序列編號:1之核苷酸序列的第一編碼序列編碼而成;該CDR-L2是由一包含序列編號:2之核苷酸序列的第二編碼序列編碼而成;該CDR-L3是由一包含序列編號:3之核苷酸序列的第三編碼序列編碼而成;該CDR-H1是由一包含序列編號:4之核苷酸序列的第四編碼序列編碼而成;該CDR-H2是由一包含序列編號:5之核苷酸序列的第五編碼序列編碼而成;且該CDR-H3是由一包含序列編號:6之核苷酸序列的第六編碼序列編碼而成。
依據IUPAC代碼,在序列編號:1-6的核苷酸序列中,A代表腺嘌呤(adenine);C代表胞嘧啶(cytosine);G代表鳥糞嘌呤(guanine);T代表胸腺嘧啶(thymine);B代表C、G或T中任一核苷酸;D代表A、T或G中任一核苷酸;H代表A、C或T中任一核苷酸;K代表G或T;M代表A或C;N代表A、T、C或G中任一核苷酸;R代表A或G;S代表G或C;V代表A、C或G中任一核苷酸;W代表A或T;而Y則代表C或T。
依據某些實施方式,由噬菌體表現之scFv抗體庫包含至少四種由噬菌體表現之scFv (亦即,第一、第二、第三及第四由噬菌體表現之scFv),其中各由噬菌體表現的scFv包含分別由第一至第六編碼序列編碼而成的CDR。依據某些實施方式。依據一實施方式,所述第一由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:7、8、9、10、11及12的胺基酸序列;所述第二由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:13、14、15、16、17及12;所述第三由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:7、18、19、20、21及22;以及所述第四由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:23、24、25、26、27及12。
由噬菌體表現的scFv抗體庫是經蛋白A及蛋白L篩選建構而成,因此各個由噬菌體表現的scFv皆具有一可結合至蛋白A的VH域,以及一可結合至蛋白L的VL域。此外,該由噬菌體表現的scFv抗體庫也經過目標抗原(例如,MSLN等TAA)篩選,以確保各個由噬菌體表現的scFv對目標抗原(例如,MSLN等TAA)具有結合親和力及/或專一性。可依據美國專利申請案10,336,816 B2所述方法來建構該些由噬菌體表現的scFv抗體庫。
依據某些實施方式,用以表現scFv的噬菌體為M13噬菌體或T7噬菌體。較佳地,本發明由噬菌體表現之scFv抗體庫的每一噬菌體皆帶有單一個噬質體。
依據一實施方式,由本發明由噬菌體表現之scFv抗體庫表現的scFv具有完整折疊的結構;具體來說,該些scFv可表現於噬菌體表面,或是表現為可分泌之可溶形式。
(II-2)
自噬菌體表現之
scFv
抗體庫篩選抗體片段
建構所述scFv抗體庫以有效辨認一抗體片段,其係對目標抗原(例如TAA (像是MSLN))具有結合親和力及/或專一性。自該scFv抗體庫來篩選一對目標抗原具有專一性之抗體片段的方法包含以下步驟:
(a) 將由噬菌體表現的scFv抗體庫暴露於目標抗原中;
(b) 自步驟(a)之該由噬菌體表現的scFv抗體庫中篩選出複數個噬菌體,其分別表現對目標抗原具有結合親和力的scFv;
(c) 分別使步驟(b)篩選出的複數個噬菌體表現出複數個可溶形式的scFv;
(d) 將步驟(c)之複數個可溶形式的scFv暴露於目標抗原中;
(e) 分別確認步驟(d)中的複數個可溶形式的scFv對該目標抗原的結合親和力;以及
(f) 基於步驟(e)所確定的結果,從複數個可溶形式的scFv中選取一對目標抗原之結合親和力優於其他可溶形式的scFv之可溶形式的scFv做為抗體片段。
在步驟(a)中,將該scFv抗體庫暴露於目標抗原或其片段。依據某些實施方式,該目標抗原是MSLN。
在步驟(b)中,自scFv抗體庫中篩選出複數個噬菌體,其中經篩選出的噬菌體會分別表現對目標抗體(如,MSLN)具有結合親和力的scFv。具體來說,是以沖提緩衝液處理步驟(b)的產物,該緩衝液通常為酸性溶液(例如甘胺酸溶液,pH 2.2),據以破壞目標抗原與由噬菌體表現的scFv之間的結合。藉由此種方法,收集複數個分別表現對目標抗原具有結合親和力之scFv的噬菌體。
非必要地,於酸性條件下進行步驟(b)。具體來說,步驟(b)的產物可進行酸處理(舉例來說,利用pH值在5-7之間的洗滌緩衝液,例如利用pH為5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9或7的洗滌緩衝液;較佳地,利用pH值為5.0的洗滌緩衝液),接著進行前述沖提步驟以收集該些噬菌體。
接著,在步驟(c)中,使步驟(b)篩選出的複數個噬菌體表現/製備複數個可溶形式之scFv。可利用習知方法來進行此步驟。依據本揭示內容某些實施方式,可利用乳糖操縱子(lac operon)來驅動VH域和VL域的表現;如本領域技術人員所熟知,可藉由異丙基-硫代-β-D-半乳糖苷(isopropyl-thio-β-D-galactoside, IPTG)來引發乳糖操縱子,進而驅動下游基因(即用以編碼VH域和VL域的基因)的表現。產生的scFv因此會分泌至培養液之上清液中,習知技藝人士可由此收集該些scFv。
在步驟(d)中,分別將步驟(c)製備的可溶形式的scFv與目標抗原混合,以形成抗原-scFv複合體。
接下來,在步驟(e)中,可利用本領域具有通常知識者所熟知之用於分析兩個分子之間的結合親和力(例如,抗體對抗原的結合親和力)的方法來決定步驟(d)中形成抗原-scFv複合體的量;舉例來說,可利用酵素連結免疫吸附檢定(enzyme-linked immunosorbent assay, ELISA)、西方墨點法(western blotting, WB)、流式細胞儀(flow cytometry)、表面電漿共振(surface plasmon resonance, SPR)或側流式免疫檢定法(lateral flow immunoassay, LFIA)等方法來決定。一般而言,抗原-scFv複合體的量會與scFv和抗原之間的結合親和力成正比。
最後,在步驟(f)中,基於步驟(e)決定的結合親和力來篩選抗體片段。更具體來說,是自複數個可溶形式的scFv中挑選出一scFv作為抗體片段,其中相較於其他scFv,挑選出的scFv對目標抗原(例如,MSLN)具有更佳的結合親和力。
依據非必要的實施方式,該方法更包含於步驟(d)前,將步驟(c)之複數個可溶形式的scFv暴露於蛋白A及/或蛋白L,據以篩選出對蛋白A及/或蛋白L具有結合親和力之可溶形式的scFv。依據可選擇的實施方式,該方法更包含於步驟(f)後,將步驟(f)之複數個可溶形式的scFv暴露於蛋白A及/或蛋白L,以確保選出之可溶形式的scFv對蛋白A及/或蛋白L具有結合親和力。
依據本揭示內容某些實施方式,將經過不同篩選程序篩選出來的四種抗體片段分別命名為「CHS5 scFv」、「CHS7 scFv」、「CHS8 scFv」及「ALA12 scFv」。
(II-3)
重組抗體或其片段
自本發明scFv抗體庫篩選出的抗體片段可用以製備一完整抗體(例如,一IgG抗體)或不同種類的抗體片段(例如,Fab、Fab’或F(ab’)2)。利用本領域所習知的方法來製備完整抗體或抗體片段,舉例來說,可以美國專利申請案US 10,336,815 B2或US 10,336,816 B2所述之相同方法來製備。依據某些實施方式,是將4種完整抗體製備為重組IgG抗體的形式,其中除了篩選出之scFv的VL域及VH域外,完整抗體更包含免疫球蛋白的輕鏈恆定(light chain constant, CL)域及重鏈恆定(heavy chain constant, CH)域;在該些實施方式中,重組IgG抗體分別命名為「CHS5 IgG」、「CHS7 IgG」、「CHS8 IgG」及「ALA12 IgG」。由該方法製備的重組抗體及其片段(例如scFv、Fab、Fab’或F(ab’)2)皆涵蓋在本揭示內容的範圍中。
當可理解,亦可以DNA選殖來製備本發明抗體(包含重組IgG抗體及其片段)。具體來說,本領域具有通常知識者可基於本揭示內容建構一包含本發明抗體之CDR序列的DNA表現載體,接著將該DNA表現載體導入宿主細胞(例如,大腸桿菌(
E.coli)細胞、猴COS細胞(simian COS cell)、中國倉鼠卵巢(Chinese hamster ovary, CHO)細胞或骨髓瘤細胞等不會產生免疫球蛋白的細胞)中,據以在宿主細胞中合成所欲抗體。
依據本揭示內容實施方式,各抗體皆包含一VL域及一VH域,其中VL域及VH域分別包含三個CDR (亦即於VL域中的CDR-L1、CDR-L2和CDR-L3,以及於VH域中的CDR-H1、CDR-H2和CDR-H3)。將本發明抗體或其片段的CDR序列總結於表1。
表1 特定抗體的胺基酸序列
CHS5 (序列編號) | CHS7 (序列編號) | CHS8 (序列編號) | ALA12 (序列編號) | |
CDR-L1 | RASQDVKEGVA (7) | RASQDVEDGVA (13) | RASQDVKEGVA (7) | RASQDVRDGVA (23) |
CDR-L2 | DQSHRLYS (8) | GIKDLLYS (14) | DERERLYS (18) | DQMVRLYS (24) |
CDR-L3 | QQYYAWPST (9) | QQYYRWPST (15) | QQYNTWPAT (19) | QQYFNWPVT (25) |
CDR-H1 | AASGFTITDRTIH (10) | AASGFTIDKEAIH (16) | AASGFTISKASIH (20) | AASGFTIGNWTIH (26) |
CDR-H2 | SIFPTKGVTT (11) | SIYPHSGFTL (17) | SIWPTKGFTT (21) | LIWPESGATL (27) |
CDR-H3 | ARGRYWMDY (12) | ARGRYWMDY (12) | ARGRYWLDY (22) | ARGRYWMDY (12) |
依據某些實施方式,本發明CHS5抗體(例如,CHS5 IgG或CHS5 scFv)的VL域包含與序列編號:28具有至少85% (例如,85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)之序列相似度的胺基酸序列,且VH域包含與序列編號:29具有至少85% (例如,85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)之序列相似度的胺基酸序列。當可理解,該VL域及VH域的序列(例如框架序列)可能會有所不同(例如,經保守性或非保守性的胺基酸殘基所置換),但不影響本揭示內容之抗體的結合親和力及/或專一性。較佳地,該VL域及VH域的序列是經一或多個具有相似特性的適當胺基酸進行保守性置換;舉例來說,將白胺酸(一種非極性胺基酸殘基)置換成異白胺酸、丙胺酸、纈胺酸、脯胺酸、苯丙胺酸或色胺酸(另一種非極性胺基酸殘基);將天門冬胺酸(一種酸性胺基酸殘基)置換成麩胺酸(另一種酸性胺基酸殘基);或是將離胺酸(一種鹼性胺基酸殘基)置換成精胺酸或組胺酸(另一種鹼性胺基酸殘基)。依據某些較佳的實施方式,本發明CHS5抗體(例如CHS5 IgG或CHS5 scFv)的VL域及VH域分別包含與序列編號:28及29具有至少90%之序列相似度的胺基酸序列。更加地,本發明CHS5抗體(例如CHS5IgG或CHS5 scFv)的VL域及VH域分別包含與序列編號:28及29具有至少95%之序列相似度的胺基酸序列。在一例示性實施方式中,本發明CHS5抗體(例如CHS5IgG或CHS5 scFv)的VL域包含序列編號:28的胺基酸序列(亦即包含與序列編號:28具有100%之序列相似度的胺基酸序列),且本發明CHS5抗體(例如CHS5IgG或CHS5 scFv)的VH域包含序列編號:29的胺基酸序列(亦即包含與序列編號:29具有100%之序列相似度的胺基酸序列)。
依據某些實施方式,本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VL域包含與序列編號:30具有至少85%之序列相似度的胺基酸序列,且本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VH域包含與序列編號:31具有至少85%之序列相似度的胺基酸序列。依據某些較佳的實施方式,本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VL域及VH域分別包含與序列編號:30及31具有至少90%之序列相似度的胺基酸序列。更佳地,本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VL域及VH域分別包含與序列編號:30及31具有至少95%之序列相似度的胺基酸序列。在一例示性實施例中,本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VL域包含序列編號:30的胺基酸序列,且本發明CHS7抗體(例如CHS7 IgG或CHS7 scFv)的VH域包含序列編號:31的胺基酸序列。
依據某些實施方式,本發明CHS8抗體(例如CHS8 IgG或CHS scFv)的VL域包含與序列編號:32具有至少85%之序列相似度的胺基酸序列,且本發明CHS8抗體(例如CHS8 IgG或CHS8 scFv)的VH域包含與序列編號:33具有至少85%之序列相似度的胺基酸序列。依據某些較佳的實施方式,本發明CHS8抗體(例如CHS8 IgG或CHS8 scFv)的VL域及VH域分別包含與序列編號:32及33具有至少90%之序列相似度的胺基酸序列。更佳地,本發明CHS8抗體(例如CHS8 IgG或CHS8 scFv)的VL域及VH域分別包含與序列編號:32及33具有至少95%之序列相似度的胺基酸序列。在一例示性實施例中,本發明CHS8抗體(例如CHS8 IgG或CHS8 scFv)的VL域包含序列編號:32的胺基酸序列,且本發明CHS8抗體(例如CHS8 IgG或CHS8 scFv)的VH域包含序列編號:33的胺基酸序列。
依據可選擇的實施方式,本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VL域包含與序列編號:34具有至少85%之序列相似度的胺基酸序列,且本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VH域包含與序列編號:35具有至少85%之序列相似度的胺基酸序列。依據某些較佳的實施方式,本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VL域及VH域分別包含與序列編號:34及35具有至少90%之序列相似度的胺基酸序列。更佳地,本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VL域及VH域分別包含與序列編號:34及35具有至少95%之序列相似度的胺基酸序列。在一例示性實施例中,本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VL域包含序列編號:34的胺基酸序列,且本發明ALA12抗體(例如ALA12 IgG或ALA12 scFv)的VH域包含序列編號:35的胺基酸序列。
依據本揭示內容某些實施方式,各抗體皆對MSLN具有結合親和力及/或專一性。
(II-4)
免疫偶聯物及包含該免疫偶聯物的藥學組合物
本發明抗體可用以建構一用以治療癌症(例如,具有MSLN表現之癌症)的ADC。據此,本揭示內容的另一態樣係關於一種免疫偶聯物,其在結構上包含一本揭示內容之抗體(例如重組IgG抗體或其片段,例如scFv)、一功能性模體及一用以連接功能性模體及抗體的連接子。
依據一例示性實施方式,該抗體為CHS5抗體(例如CHS5 scFv或CHS5 IgG),且包含序列編號:7 (CDR-L1)、序列編號:8 (CDR-L2)、序列編號:9 (CDR-L3)、序列編號:10 (CDR-H1)、序列編號:11 (CDR-H2)及序列編號:12 (CDR-H3)的胺基酸序列。依據另一例示性實施方式,該重組抗體/抗體片段為抗體CHS7 (例如CHS7 scFv或CHS7 IgG),且包含序列編號:13 (CDR-L1)、序列編號:14 (CDR-L2)、序列編號:15 (CDR-L3)、序列編號:16 (CDR-H1)、序列編號:17 (CDR-H2)以及序列編號:12 (CDR-H3)的胺基酸序列。依據又一例示性實施方式,該重組抗體/抗體片段為抗體CHS8 (例如CHS8 scFv或CHS8 IgG),且包含序列編號:7 (CDR-L1)、序列編號:18 (CDR-L2)、序列編號:19 (CDR-L3)、序列編號:20 (CDR-H1)、序列編號:21 (CDR-H2)及序列編號:22 (CDR-H3)的胺基酸序列。依據又一例示性實施方式,該重組抗體/抗體片段為抗體ALA12 (例如ALA12 scFv或ALA12 IgG),且包含序列編號:23 (CDR-L1)、序列編號:24 (CDR-L2)、序列編號:25 (CDR-L3)、序列編號:26 (CDR-H1)、序列編號:27 (CDR-H2)及序列編號:12 (CDR-H3)的胺基酸序列。
該功能性模體包含一治療劑,以及一非必要之與治療劑連接的ER滯留胜肽(例如KDEL(序列編號:36))。依據所欲目的不同,治療劑可以是一免疫毒素、一免疫脂質體或一細胞毒性藥物。免疫毒素的非限制實例包含,白喉A次單元(diphtheria A subunit)、白喉毒素的非結合片段、外毒素A次單元、蓖麻毒素A (ricin A)次單元、思豆毒素A (abrin A) 次單元、莫迪素A (modeccin A ) 次單元、α-八疊球菌(alpha-sarcin)、油桐蛋白(Aleurites fordii protein)、香石竹毒蛋白(dianthin protein)、美洲商陸蛋白 (Phytolacca americana protein, PAP) (PAPI、PAPII 及 PAP-S)、苦瓜抑制因子(momordica charantia inhibitor)、痲瘋樹毒蛋白(curcin)、巴豆毒素(crotin)、肥皂草抑制劑(sapaonaria officinalis inhibitor)、白樹毒素(gelonin)、米托菌素(mitogellin)、局限曲菌素(restrictocin)、酚黴素(phenomycin)及伊諾黴素(enomycin)。依據某些較佳的實施方式,該免疫毒素為外毒素;更佳地,該免疫毒素為 綠膿桿菌外毒素(
Pseudomonas Exotoxin, PE)或其衍生物。在本揭示內容一操作性實施例中,該免疫毒素為截斷的PE A次單元毒素。
細胞毒性藥物的實例包含,但不限於,抗雌性素(anti-estrogen,如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)及甲地孕酮(megestrol))、黃體釋素促效劑(LHRH agonist,如戈舍瑞林(goscrclin)及亮丙瑞林(leuprolide))、抗雄性素(anti-androgen,如氟他胺(flutamide)及比卡魯胺(bicalutamide))、光動力治療劑(photodynamic therapies,如維替泊芬(vertoporfin) (BPD-MA)、酞菁(phthalocyanine)、光敏劑Pc4 (photosensitizer Pc4) 及去甲氧基竹紅菌素(demethoxy-hypocrellin A)(2BA-2-DMHA))、氮芥(nitrogen mustard,如環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、氯乙環磷醯胺(trofosfamide)、苯丁酸氮芥(chlorambucil)、雌莫司汀(estramustine)及美法崙(melphalan))、亞硝基尿素(nitrosoureas,如卡莫司汀(carmustine)(BCNU)及洛莫司汀(lomustine)(CCNU))、烷基磺酸(alkylsulphonate,如白消安(busulfan)及蘇消安(treosulfan))、三氮烯(triazene,如達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide))、含鉑化合物(如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin))、長春花生物鹼(vinca alkaloid,如長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))、類紫杉醇(taxoid,如紫杉醇(paclitaxel)或紫杉醇等效物(paclitaxel equivalent),像是與奈米顆粒白蛋白結合的紫杉醇二十二碳六烯酸結合的紫杉醇 (docosahexaenoic acid bound-paclitaxel) (DHA-紫杉醇(DHA-paclitaxel)、紫杉素(taxoprexin))、聚谷胺酸結合的紫杉醇 (polyglutamate bound-paclitaxel)(PG-紫杉醇(PG-paclitaxel)、聚谷胺酸紫杉醇(paclitaxel poliglumex))、活化腫瘤的前驅(the tumor-activated prodrug, TAP) ANG1005 (與紫杉醇的三個分子結合的血管胜肽素2 (angiopep-2))、紫杉醇EC-1 (paclitaxel-EC-1) (與識別erbB2的胜肽EC-1 (erbB2-recognizing peptide EC-1)結合的紫杉醇)、和葡萄糖耦接的紫杉醇(例如2’-紫杉醇甲基2-葡萄糖基吡喃糖基琥珀酸酯(2’-paclitaxel methyl 2-glucopyranosyl succinate));歐洲紫杉醇(docetaxeal)、紫杉醇(taxol))、表鬼臼毒素(epipodophyllin,如依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)、替尼泊苷(teniposide)、托泊替康(topotecan)、9-胺基喜樹鹹(9-aminocamptothecin)、康托替康(camptoirinotecan)、伊立替康(irinotecan)、甲磺酸(crisnatol)及絲裂黴素C (mytomycin C))、抗代謝藥物(anti-metabolite)、二氫葉酸還原酶抑制劑(DHFR inhibitor,如胺甲喋呤(methotrexate)、二氯甲胺蝶呤(dichloromethotrexate)、三甲蝶呤(trimetrexate)及依達曲沙(edatrexate))、肌苷-5’-單磷酸去氫酶抑制劑(IMP dehydrogenase inhibitor,如黴酚酸(mycophenolic acid)、噻唑呋林(tiazofurin)、利巴韋林(ribavirin)及EICAR)) 、核糖核苷酸還原酶抑制劑(ribonuclotide reductase inhibitor,如羥基尿素(hydroxyurea)及去鐵胺(deferoxamine))、尿嘧啶類似物(如5-氟尿嘧啶(5-fluorouracil,5-FU)、氟尿苷(floxuridine)、去氧氟尿苷(doxifluridine)、雷替曲塞(ratitrexed)、替加氟尿嘧啶(tegafur-uracil)及卡培他濱(capecitabine))、胞嘧啶類似物(如阿糖胞苷(cytarabine,又稱ara C)、胞嘧啶阿糖胞苷(cytosine arabinoside)及氟達拉濱(fludarabine))、嘌呤類似物(如硫氫基嘌呤(mercaptopurine)及硫鳥嘌呤(Thioguanine))、維生素D3類似物(如EB 1089、CB 1093及KH 1060)、異戊二烯抑制劑(isoprenylation inhibitor,如洛伐他汀(lovastatin))、多巴胺能神經毒素(dopaminergic neurotoxin,如1-甲基-4-苯基吡啶離子(1-methyl-4-phenylpyridinium ion))、細胞週期抑制劑(如星形孢菌素(staurosporine))、放線菌素(actinomycin,如放線菌素D、放線菌素)、博萊黴素(bleomycin,如博萊黴素A2、博萊黴素B2及培洛黴素(peplomycin))、蒽環類藥物(anthracycline,如柔紅黴素(daunorubicin)、阿黴素(doxorubicin)、聚乙二醇化脂質體阿黴素(pegylated liposomal doxorubicin)、伊達比星(idarubicin)、表柔比星(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)及米托蒽醌(mitoxantrone) 多重抗藥性抑制劑(MDR inhibitor,如維拉帕米(verapamil))、鈣離子三磷酸腺苷酶抑制劑(Ca
2+ATPase inhibitor,如毒胡蘿蔔素(thapsigargin))、伊馬替尼(imatinib)、沙利度胺(thalidomide)、來那度胺(lenalidomide)、酪胺酸激酶抑制劑(tyrosine kinase inhibitor,如阿西替尼(axitinib)、波舒替尼(bosutinib)、西地尼布(cediranib)、達沙替尼(dasatinib)、厄羅替尼(erlotinib)、吉非替尼(gefitinib)、伊馬替尼(imatinib)、拉帕替尼(lapatinib)、來他替尼(lestaurtinib)、那替尼(neratinib)、尼洛替尼(nilotinib)、司馬沙尼(semaxanib)、舒尼替尼(sunitinib)、托賽拉尼(toceranib)、凡德他尼(vandetanib)、瓦他拉尼(vatalanib)、曲妥珠單抗(trastuzumab)、貝伐單抗(bevacizumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)、雷尼單抗(ranibizumab)、尼洛替尼(nilotinib)、索拉非尼(sorafenib)、依維莫司(everolimus)、阿崙單抗(alemtuzumab)、吉美他莫唑加敏(gemtuzumabozogamicin)、替西羅莫司(temsirolimus)、乳酸多維替尼(dovitinib lactate)及蒂沃扎尼(tivozanib))、蛋白酶抑制劑(如硼替佐米(bortezomib))、哺乳類斥消靈標的蛋白抑制劑(mTOR inhibitor,例如雷帕黴素(rapamycin)、西羅莫司(temsirolimus)、依維莫司(everolimus)、及雷帕黴素衍生物(ridaforolimus))、奧利默森(oblimersen)、吉西他濱(gemcitabine)、洋紅黴素(carminomycin)、亞葉酸鈣(leucovorin)、培美曲塞(pemetrexed)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、甲基芐肼(procarbizine)、潑尼松龍(prednisolone)、地塞米松(dexamethasone)、喜樹鹼(campathecin)、普卡黴素(plicamycin)、天門冬醯胺酶(asparaginase)、胺基蝶呤(aminopterin)、甲胺蝶呤(methopterin)、紫菜黴素(porfiromycin)、美法崙(melphalan)、異長春鹼(leurosidine)、環氧長春鹼(leurosine)、苯丁酸氮芥(chlorambucil)、曲貝替定(trabectedin)、丙卡巴肼(procarbazine)、海綿內酯(discodermolide)、洋紅黴素(carminomycin)、胺基蝶呤(aminopterin)或六甲基三聚氰胺(hexamethyl melamine)。依據本揭示內容一特定實施例,該細胞毒性藥物為澳瑞他汀或其衍生物(例如MMAE或MMAF)。
該免疫脂質體至少包含一治療劑(例如免疫毒素及/或細胞毒性藥物)包覆於脂質體的結構中。依據所欲之目的,該脂質體可以是一大型單層載體(large unilamellar vesicle, LUV)、多層載體( multilamellar vesicle, MLV)或是小型單層載體(small unilamellar vesicle, SUV)。
該連接子可以是纈胺酸-瓜胺酸(valine-citrulline, vc)雙胜肽、多胜肽、DNA、RNA、脂肪鏈或適體。依據本揭示內容某些實施方式,該連接子為纈胺酸-瓜胺酸雙胜肽;在該些實施方式中,免疫偶聯物是以IgG-vc-藥物的形式存在,其中該治療劑(例如MMAE)是與透過纈胺酸-瓜胺酸雙胜肽與IgG抗體的半胱胺酸殘基連接。依據本揭示內容某些實施方式,該連接子為一具有「ASAAGGSGT」(序列編號: 37)之胺基酸序列的多肽;據以產生的免疫偶聯物自N-端到C-端依序包含一抗體、一多肽及一功能性模體PE38KDEL,其中功能性模體PE38KDEL包含截斷的PE A次單元毒素(亦即PE38)以及一ER滯留胜肽(亦即KDEL,序列編號:36)。依據本揭示內容可選擇地實施方式,連接子是包含一或多個AL模組的適體,其中各AL模組各包含一位於N-端的蛋白A片段、一位於C-端的蛋白L片段,以及一連接蛋白A及蛋白L片段的多肽。在一操作性實施例中,IgG抗體藉由一AL模組與一包含序列編號:38之胺基酸序列的功能性模體(例如,PE38KDEL)連接。
以本領域具有通常知識者熟知的方法來建構ADC。可選擇地,可依據美國專利申請號10,752,673 B2或10,562,976 B2中所述之方法來製備本發明免疫偶聯物。
本揭示內容亦提供一種藥學組合物,其包含依據本揭示內容任一實施方式的免疫偶聯物以及藥學上可接受之賦形劑。
一般來說,本發明免疫偶聯物是以重量比0.01%至99.9%的比例存在於該藥學組合物中。在某些實施方式中,該免疫偶聯物是以重量比至少0.1%的比例存在於該藥學組合物中。在某些實施方式中,該免疫偶聯物是以重量比至少5%的比例存在於該藥學組合物中。在其他實施方式中,該免疫偶聯物是以該藥學組合物之總重量的至少10%的比例存在於其中。又其他實施方式中,該免疫偶聯物是以該藥學組合物之總重的至少25%的比例存在於其中。
較佳地,本發明藥學組合物是配製成液體形式,例如溶液、栓劑及注射劑。在此情況下,可以像是靜脈內、動脈內、腹膜內或瘤内注射(intratumoral injection)的方式投予本發明免疫偶聯物。在藥學劑量形式上,本發明免疫偶聯物可以是單獨給藥,或是與其他已知用以治療由癌症引起或相關的疾病或障礙的藥學活性劑合併給藥。本領域中具有通常知識者熟知適用於不同給藥途徑的多種劑量形式。值得注意的是,用以治療該疾病或障礙的最佳給藥途徑是取決於其特性或嚴重度。
(II-5)
治療癌症的方法
本揭示內容的另一態樣是關於一種治療一個體之癌症的方法,特別是MSLN-陽性的癌症(亦即,會表現MSLN的癌症)。所述方法包含投予該個體一有效量的本發明免疫偶聯物或本揭示內容任一態樣及實施方式的藥學組合物。
在一實施方式中,該個體為小鼠。為了在小鼠體內產生治療功效,是將每劑量為每公斤體重0.1至1,000毫克的免疫偶聯物投予至小鼠(亦即,投予每劑為每公斤體重0.1至1,000毫克的本發明免疫偶聯物至個體;可選擇地,當投予該藥學組合物至個體中,每劑的量提高至每公斤體重0.1至1,000毫克的該免疫偶聯物);舉例來說,每劑為每公斤體重0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950或1,000毫克。較佳地,投予每劑為每公斤體重1至100毫克的本發明免疫偶聯物。依據一操作性實施例,每劑每公斤體重10至20毫克的該免疫偶聯物即可在個體中產生對腫瘤具有專一性的細胞毒性反應(例如抑制腫瘤生長)。
本發明所屬技術領域中具有通常知識者可以根據動物模型的劑量,計算出該免疫偶聯物的人類等效劑量(human equivalent dose, HED)。據此,適用於人類個體的該免疫偶聯物之有效量範圍是介於每劑每公斤體重0.01至100毫克;舉例來說,每劑每公斤體重0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100毫克。較佳地,有效的HED是每劑每公斤體重約0.1至10毫克。在一較佳的實施例中,該有效的HED是每劑每公斤體重約1至2毫克。
該免疫偶聯物或該藥學組合物的有效量會依據多種因素有所不同,舉例來說,該因素可能是患者的身體狀況(例如患者的體重、年齡或性別)、障礙的嚴重度、哺乳類或動物的種類、治療的週期、同步治療(若有)的特性、特定投予途徑及其他健康從業人員的知識及專長範圍內的類似因素。
重複投予數天或更長(取決於身體狀況),該治療持續至產生所欲之抑制症狀的效果,或達到足以減緩癌症或症狀的治療效果。依據本揭示內容某些實施方式,至少投予兩次本發明免疫偶聯物或藥學組合物至該個體,例如投予2、3、4、5或更多次。投予的頻率可以是每日一次、每2天一次、每3天一次、每4天一次、每5天一次、每6天一次、每週一次、每2週一次、每3週一次、每個月一次、每2個月一次、每3個月一次或是更長。在一操作性實施例中,是連續3週,每週投予一次本發明免疫偶聯物。
該免疫偶聯物或藥學組合物可以靜脈內、動脈內、腹膜內、病灶內(intralesionally)或瘤內投予的方式給藥。依據一實施方式,該免疫偶聯物/藥學組合物是以靜脈內給藥投予至該個體。
適用以本發明方法治療的癌症為胃癌、肺癌、膀胱癌、乳癌、胰臟癌、腎癌、大腸直腸癌、子宮頸癌、卵巢癌、腦瘤、前列腺癌、肝細胞癌、黑色素瘤、食道癌、多發性骨髓瘤或是頭頸部鱗狀細胞癌。依據一實施方式,該癌症為胃癌。依據另一實施方式,該癌症為胰臟癌。
該個體為哺乳類,例如人類、小鼠、大鼠、猴子、綿羊、山羊、貓、狗、馬或猩猩。較佳地,該個體為人類。
當可想見,本發明方法可單獨或與有益於癌症治療的治療方法共同施予該個體。依據使用/治療目的,可在投予額外的治療之前、期間或之後對該個體施用本發明方法。
為了使本揭示內容的敘述更加詳盡與完備,下文針對了本發明的實施態樣與具體實施例提出了說明性的描述;但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而,亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
實施例
材料與方法
最適化由親本抗體衍生之抗體之
CDR
序列的方法
在此研究中,以M9 scFv (CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:39-44之胺基酸序列)作為親本模板,分別建構6種合成的scFv抗體庫,其中每個合成的scFv抗體庫包含簡併密碼子(degenerate codon, NNK)以多樣化M9的單一CDR上選定的殘基位置,同時不改變M9模板上的其他序列。以M13噬菌體表現系統各自表現該些合成的scFv抗體庫,且將該些scFv抗體庫作為噬菌體表現篩選的輸入(input),用以篩選出對經固定的MSLN具結合性的合成scFv抗體。當經篩選之M9的scFv CDR-變異型(亦即具有經多樣化之CDR的scFv,其中該CDR序列源自M9)與MSLN的結合模式仍受到M9模板的恆定CDR鎖定,可預期篩選出來經多樣化的CDR可進一步增強相應的CDR與MSLN的原位交互作用。6種噬菌體表現的scFv抗體庫分別進行與MSLN結合的3循環噬菌體表現篩選後,選出可正確摺疊(可與蛋白A及蛋白L結合)且會與MSLN結合的scFv,並定序以分析CDR序列。確認序列後,利用PCR分別自噬菌體表現篩選出的輸出抗體庫中,擴增經簡併密碼子-多樣化的CDR;PCR擴增引子對是依據M9模板進行設計並具有重疊序列,這樣的方式使另一輪PCR擴增可利用一基於M9模板設計的引子對來擴增6種PCR產物之混合物,以完成scFv抗體庫,其中該scFv抗體庫具有經優化篩選以增強CDR與MSLN上的M9抗原決定區之交互作用的CDR序列。再次以M13噬菌體表現系統表現該組合的抗體庫,並將其作為2循環的噬菌體表現篩選的輸入,篩選出可與MSLN結合的scFv抗體。自單一菌落的大腸桿菌獲得個別scFv的噬質體,其中該噬質體源自用以篩選及定性可溶形式的scFv抗體庫的輸出。篩選並定序與蛋白A、蛋白L及MSLN結合之M9的scFv CDR-變異型。
將研究中選出的4種M9 scFv CDR-變異型分別命名為「CHS5 scFv」、「CHS7 scFv」、「CHS8 scFv」及「ALA12 scFv」。
細胞株
人類胃癌細胞株NCI-N87 (ATCC CRL-5822)、人類肺癌細胞株 NCI-H226 (ATCC CRL-5826)、以及人類胰臟癌細胞株Capan-2 (ATCC HTB-80)取自美國典型培養物保藏中心(American Type Culture Collection、ATCC)。將NCI-N87及NCI-H226細胞培養於提供10%胎牛血清(fetal bovine serum)及1倍抗真菌藥的RPMI-1640培養基中,培養環境為37°C,含5% CO
2的潮濕培養箱中。將Capan-2細胞培養於提供10%胎牛血清及1倍抗真菌藥的McCoy’s 5A培養基(ATCC-20-2007)中,培養環境為37°C,包含5% CO
2的潮濕培養箱。將自NCI-60細胞庫中獲得的OVCAR-8、OVCAR-5、IGR OV1、M14、UO-31、HOP-62、PC-3、HT-29、T-47D以及SNB-19細胞株培養於提供10%胎牛血清、2 mM的L-麩醯胺酸及1倍抗真菌藥的RPMI 1640培養基中。
以流式細胞移偵測細胞表面上標示有
AL1-RFP
之
scFv
的平均螢光強度
(mean fluorescence intensity, MFI)
利用表現MSLN的培養細胞,並以流式細胞儀來確認scFv CDR-變異型的結合特徵。首先,刮下細胞並通過40微米孔徑的過濾器。將約2×10
5個細胞與100微升的scFv於4°C的環境反應30分鐘,接著以含0.5%FBS的1倍PBS (洗滌緩衝液)洗滌一次,再與含有1微克AL1-RFP的50微升洗滌緩衝液混合,於4°C的環境反應20分鐘,接著以洗滌緩衝液洗滌兩次。離心且重新懸浮後,以流式細胞儀分析細胞的紅色螢光蛋白(red fluorescent protein, RFP)的訊號。利用軟體分析數據。以MFI表示scFv與表現MSLN的細胞間結合的親和力
scFv
的細胞毒性檢定
於96孔盤中的每孔洞種10
4個細胞。室溫下,將0.5 nM的scFv於AL1-PE38KDEL中(莫耳比率為1:1)預培養1小時,據以產生非共價連接的免疫毒素。將scFv-AL1-PE38KDEL混合物加至不含血清的細胞培養液中。在37°C的環境中培養4小時後,將抗體毒素混合物以包含血清的新鮮正常培養基取代。在37°C培養4天後,測量OD450以定量存活細胞數。計算細胞活性百分比。
製備
IgG1
將重組IgG載體轉染至EXPI293F
TM細胞來生產IgG1抗體。EXPI293F
TM保存於包含EXPI293™表現培養基的附通氣蓋之震盪錐形瓶中,以維持較佳的活性。依據製造商的指引以轉染套組進行轉染。培養3天後,利用蛋白A樹脂親和性管柱純化上清液中的抗體。以十二烷基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate-polyacrylamide electrophoresis, SDS-PAGE)及分光光度測定法分析抗體的純度及濃度。
疏水性交互作用層析
(hydrophobic interaction chromatography, HIC)
製備緩衝液A (50毫莫耳濃度(mM)磷酸鉀緩衝液,pH7.2;1.5莫耳濃度(M)硫酸銨)及緩衝液B (50毫莫耳濃度(mM)磷酸鉀緩衝液,pH7.2)。首先,以含有20%:80%的緩衝液B:A進行蛋白質待測物的沉澱測試。將蛋白質待測物溶液以13,000轉的速度離心3分鐘,使蛋白質待測物集中於上清液,接著以分光光度測定法確認濃度。以HIC分析上清液中沒有實質損失之預期濃度的蛋白質待測物。注入樣本前,以5毫升的緩衝液A平衡管柱。加入100微升蛋白質待測物(每毫升緩衝液0.5毫克,其中該緩衝液為20%:80%的緩衝液B:A)至管柱上,並進行1毫升注射環清洗。在13毫升的運行體積中完成20%:80%至90%:10%之緩衝液B:A的線性梯度。接著以1毫升比例為90%:10%之緩衝液B:A的緩衝液清洗管柱,再以4毫升比例為20%:80%之緩衝液B:A的緩衝液清洗管柱。
製備
IgG1-vcMMAE ADC
及
ADC
產量
IgG1透過經三(2-羧乙基)膦(tris(2-carboxyethyl)phosphine,TCEP)還原的IgG1上的半胱胺酸殘基與vcMMAE偶聯。簡單來說,是在室溫下與2當量的還原劑-IgG1莫爾比率的TCEP反應一小時以部份還原抗體。以N-乙醯半胱胺酸在室溫下反應30分鐘來終止反應。將經終止反應的混合物以5毫升的脫鹽管柱進行膠體過濾脫鹽;改以磷酸鹽緩衝液(phosphate-buffered saline, PBS)做為緩衝液,並以超濾離心來濃縮ADC產物。將ADC溶液通過0.2微米過濾器過濾,儲存於4°C。以SDS-PAGE分析ADC產物。IgG1-vcMMAE偶聯的ADC產量是以輸出的ADC產物內的IgG1除以輸入的IgG1總量的百分比來表示。
以
ELISA
測量
MSLN
結合的
EC
50
將含有MSLN (每孔洞0.3微克)的PBS緩衝液(pH 7.4)塗佈於96孔盤中,於4°C反應過夜,並以含有5%牛奶的PBST(0.1%(v/v) TWEEN
®20)阻斷1小時,以確認經純化的人類IgG1及IgG1-vcMMAE與MSLN結合的EC
50。同時,以2倍連續稀釋製備11種濃度的抗體/ADC (溶於含有5%牛奶的PBST),接著加入100微升經稀釋的樣本至96-孔盤中。經過1小時結合反應且以PBST洗滌三次後,加入100微升與山葵過氧化酶(horseradish peroxidase, HRP)鍵結的抗-人類IgG抗體(1:5,000倍稀釋)反應1小時。再分別以PBST洗滌三次,以PBS緩衝液洗滌兩次後,以3,3',5,5'-四甲基聯苯胺(3,3’,5,5’-tetramethyl-benzidine peroxidase, TMB)受質呈色3分鐘,然後以1.0 莫耳濃度的HCl終止反應,並讀取波長450奈米處的分光光度檢定的讀值。據以計算EC
50(nM)。
測量
IgG1-vcMMAE
及
IgG1-AL1-PE38KDEL
的細胞毒性
(IC
50)
將N87細胞種在96孔盤(每孔洞1×10
4個細胞)中以測量其細胞存活力的IC
50。測量IgG1-AL1-PE38KDEL的IC
50時,是先將IgG與AL1-PE38KDEL以莫耳比率1:2於室溫進行預培養1小時。藉由此程序形成非共價鍵結的免疫毒素。將IgG1-AL1-PE38KDEL的混合物或經純化的IgG1-vcMMAE溶液加入不含血清的培養基中。在37°C培養16小時後,以新鮮含血清的正常培養基取代,並在37°C與WST-1試劑反應72小時以檢測細胞毒性。將相應的PBS處理控制組細胞的存活力作為100%來標準化數值,並以軟體計算IC
50。
細胞毒性專一性檢定
將N87、IGR-OV1、M14、UO-31、HOP-62、PC-3、HT-29、T-47D及SNB-19細胞株的細胞種在96孔盤中(每一孔洞約2×10
4個細胞)。將不同濃度的IgG1-vcMMAE ADC直接加入含有10% FBS的培養基內。以ADC處理4天後,於每一孔洞加入10微升WST-1溶液。在37°C反應5小時後,確認波長450奈米處的吸光值。以OD450奈米的值定量細胞存活率的百分比。
異種移植小鼠模型治療
經皮下注射腫瘤細胞至8週大NOD/SCID公鼠。在每隻小鼠體內植入1×10
6個N87細胞或3×10
6個Capan-2細胞,並以抗-MSLN IgG1-vcMMAE分別處理14天或21天。當腫瘤尺寸達到80-100mm
3時,隨機指派小鼠作為控制組及處理組並開始給藥。每週一次共投予三週,以靜脈注射至小鼠尾靜脈的方式投予抗-MSLN IgG1-vcMMAE(每公斤15毫克)。連續測量每隻一種移植小鼠的腫瘤體積及體重,直到投予抗-MSLN IgG1-vcMMAE後的第35天。繪示每一處理組中每隻實驗個體於第35天的最終腫瘤體積。利用橢圓體公式(長度×寬度×高度×0.523)計算腫瘤體積。
實施例1 M9之抗-MSLN抗體CDR-變異型用以辨認抗原之CDR序列的偏好
如材料與方法所述,以抗-MSLN抗體M9作為抗-MSLN之ADC優化之CDR序列的抗體模板。源自噬菌體表現篩選輸出的M9會與MSLN結合之scFv CDR-變異型用以呈現M9的CDR序列偏好圖譜。M9會與MSLN結合之scFv CDR-變異型(亦即,CHS5 scFv、CHS7 scFv、CHS8 scFv及ALA12 scFv)的CDR序列總結於表1,其中M9會與MSLN結合之scFv CDR-變異型是指其可溶性的scFv可與MSLN、蛋白A及蛋白L結合(與蛋白L/A結合表示scFv的結構正確摺疊)。分析結果指出,CDRL3及CDRH3在M9的序列偏好圖譜中表現顯著,因此在這兩種CDR (特別是CDRL3中的L91-Y和L94-W,以及CDRH3中的H97-Y和H98-W)中某些殘基在M9的scFv CDR-變異型上形成功能性互補位(paratope)(數據未顯示)。L3及H3的CDR序列偏好的保留性反應出保留性原位CDR-抗原交互作用,表示M9的scFv CDR-變異型與M9結合至MSLN上相同的抗原決定區。其他的CDR在序列偏好上相對而言保留性較低,表示該些區域位於M9-MSLN功能性介面的週邊區域,因此scFv CDR-變異型於辨識MSLN時,對序列要求的嚴格度較低。
實施例2 以高通量體外細胞毒性及流式細胞儀結合檢定評估用以開發ADC的候選scFv
進一步評估M9會與MSLN結合之scFv CDR-變異型(亦即,CHS5 scFv、CHS7 scFv、CHS8 scFv及ALA12 scFv)的專一性及親和力;M9 scFv CDR-變異型的序列總結於上表1。每個scFv自個別的
E.coli細胞培養液被分泌至培養基中,並於培養液中獲得相應的單株scFv噬質體。為了評估該些scFv作為抗-MSLN ADC的標的模組的可行性,將可溶形式的scFv分別與AL1-RFP (蛋白A-蛋白L-紅色螢光蛋白的融合蛋白)及AL1-PE38KDEL (蛋白A-蛋白L-綠膿桿菌外毒素A)非共價鍵結,用以檢測平均螢光強度及細胞毒性。兩種檢測皆利用經培養的人類癌症細胞株N87及H226來進行,其中MSLN皆會表現於N87及H226的細胞表面。AL1-RFP及AL1-PE38KDEL分別為包含蛋白A、蛋白L以及RFP或PE38KDEL的單一多肽鏈的融合蛋白;融合蛋白中的蛋白A及蛋白L分別與scFv的重鏈及輕鏈非共價鍵結(親和力的莫耳比率為1:1 (nM))。蛋白A及蛋白L與天然折疊之scFv結構的結合並沒有受到scFv-抗原交互作用的互補位-抗原決定位之界面的影響。
篩選出的M9 scFv CDR-變異型經體外評估的結果表示,scFv-MSLN專一性結合引起由受器介導的對scFv的胞吞作用。N87細胞的AL1-RFP MFI檢測及AL1-PE38KDEL細胞毒性檢測的結果與H226細胞的檢測結果呈正相關,其R
2值分別為0.87及0.74 (數據未顯示)。高度關聯性表示該些會與MSLN結合之scFv會與兩種於其表面表現MSLN的細胞株結合,且scFv-AL1-PE38KDEL免疫毒素的細胞毒性是因為scFv結合至細胞表面的MSLN所導致,而非非專一性的細胞毒性效應。更進一步以圖表說明該些結果,其是將scFv-AL1-RFP的MFI和scFv-AL1-PE38KDEL的細胞毒性相比(數據未顯示)。N87及H226細胞中,M9 scFv CDR-變異型與MSLN結合力和其細胞存活率呈負相關,其R
2值分別為0.54及0.68 (數據未顯示),此結果與假設一致,表示scFv-AL1-PE38KDEL的細胞毒性是透過特定的scFv-MSLN結合,引起細胞表面受體介導的免疫毒素之胞吞作用所導致。相較於N87細胞,免疫毒素對H226細胞的細胞毒性較強(數據未顯示),可能的原因為相較於N87細胞,H226細胞的表面表現較多MSLN (依據H226細胞具有較高的scFv-AL1-RFP之MFI絕對值作判斷) (數據未顯示)。
實施例 3 抗體於水性環境中的溶解度為抗體作為抗-MSLN ADC之標的模組的決定因素
基於scFv-MSLN交互作用的實驗數據,將4種M9 scFv CDR-變異型(亦即CHS5 scFv、CHS7 scFv、CHS8 scFv及ALA12 scFv)重建為人類IgG框架,以更進一步評估該些IgG1作為抗-MSLN ADC之標的模組的專一性及功效。經篩選出的該些scFv大多與細胞表面的MSNT具有較強的結合能力,以及免疫毒素的細胞毒性。將由該方法製備的IgG分別命名為「CHS5 IgG」、「CHS7 IgG」、「CHS8 IgG」及「ALA12 IgG」。
由於作為ADC候選的IgG1之溶解度對於製備ADC及功效相當重要,因此以算式(1)及(2)來計算其相對親水性分數(relative hydrophilicity score, RH-score),其是以一查詢的M9 scFv CDR-變異型與IgG1-M9進行比較,來預測重建自該查詢的scFv之IgG1的溶解度:
(1)
(2)
其中類型I及II的胺基酸序列分別是由序列編號:45及46的胺基酸序列所組成。
將M9之MSLN-陽性scFv CDR-變異型的RH-分數和利用相應的scFv序列計算的CamSol分數作圖;其中CamSol分數是以CamSol電腦運算法來進行預測,其基於蛋白質序列來預測蛋白質於水溶液中實際溶解度是經過驗證,且具有一定程度的準確度。依據分布曲線,相比於親代M9的scFv,超過90%的M9 會與MSLN結合之scFv CDR-變異型具有較高的RH-分數及預測的溶解度(數據未顯示),表示經優化後,與MSLN結合的CDR序列具有較高的親水性,且在水中的溶解度較高。RH-分數及CamSol分數之間呈正相關(R
2=0.58且P-值=1.5×10
-71),表示由CamSol預測的抗體溶解度是半定量的與M9之scFv CDR-變異型的CDR序列中的親水性/帶電性胺基酸種類相關;當可想見,增加抗體的CDR中親水性/帶電性殘基的數量可增加抗體在水性環境中的溶解度。
藉由疏水性交互作用管柱(hydrophobic interaction chromatography, HIC)的滯留時間測量自篩選出的M9 scFv CDR-變異型重建的IgG1的溶解度,其中滯留時間用以表示待測蛋白的疏水性,且預期會與蛋白於水中的溶解度呈負相關。將HIC的滯留時間與重建的IgG1的RH-分數作圖。HIC的滯留時間與RH-分數呈負相關,R
2為0.40 (P-值為1.7×10
-5) (數據未顯示),大幅增加RH-分數的IgG1其親水性如預期增加,因此預測相較於IgG1-M9,IgG1在水溶液中具有較佳的溶解度(數據未顯示)。
IgG1是透過還原的雙硫鍵上的半胱胺酸殘基與vcMMAE (甲基澳瑞他汀E藉由纈胺酸-瓜胺酸雙胜肽 細胞自溶酵素-可截切的連接子鏈接至IgG1) 鍵結。所有以HIC測量其藥物-抗體比例(drug-antibody ratio, DAR) (表2)的ADC皆未形成聚集。以丁基-NPR管柱對IgG1-vcMMAE進行HIC分析,因不同vcMMAE:IgG1比例產生相對應的波峰,且以波峰的分布來計算IgG1-vcMMAE的DAR (表2)。
表2 特定IgG的結合及細胞毒性的特性
ND:無法偵測。
M9 | CHS5 | CHS7 | CHS8 | ALA12 | |
存活率 (%) - H226 | 56.7 | 21.02 | 8.67 | 72.53 | 9.1 |
存活率(%) - N87 | 80.6 | 46.08 | 48.33 | 76.1 | 44.8 |
CamSol分數 | -0.16 | 0.92 | 1.08 | 1.18 | 0.07 |
RH-分數 | 0 | 13 | 11 | 14 | 5 |
MFI (%) - H226 | 69 | 70.53 | 90.11 | 30.99 | 89 |
MFI (%) - N87 | 64 | 77.84 | 87.03 | 31.89 | 100 |
ADC產量(%) | 17.5 | 1.1 | 0.93 | 1.02 | 93.9 |
HIC滯留時間 retention time (分鐘) | 18.0 | 3.8 | 7.7 | 4.2 | 5.7 |
DAR | ND | 2.56 | 3.21 | 2.63 | 2.72 |
IgG1 EC 50(奈克/毫升) | 3.15 | 4.67 | 10.3 | 5.05 | 8.37 |
IgG1-vcMMAE EC 50(奈克/毫升) | 4.86 | 9.56 | 16.27 | 9.26 | 10.49 |
IgG1-AL1-PE38KDEL IC 50(nM) | 0.39 | 0.06 | 0.06 | 0.01 | 0.1 |
IgG1-vcMMAE IC 50(nM) | 78.13 | 15.03 | 25.95 | 24.57 | 39.94 |
抗體的親水性會增加ADC產量及vcMMAE與IgG1鍵結的DAR。ADC產量隨著RH-分數增加而提升,但兩者的正相關性較弱(R
2=0.10;P-值=0.018) (數據未顯示)。ADC的DAR (藥物-抗體比率)也隨著RH-分數增加而上升(R
2=0.15;P-值=0.10) (數據未顯示)。儘管正相關性較弱,兩者的結果表示IgG1的親水性加速vcMMAE與IgG1偶聯。此外,將IgG1-vcMMAE與MSLN結合之半最大有效濃度(MSLN-EC
50)與IgG1的MSLN-EC
50相對作圖,斜率為1.1,R
2=0.62 (P-值=1.0×10
-7)。此相關性表示vcMMAE與IgG1上還原之雙硫鍵的半胱胺酸殘基結合對於IgG1與MSLN的結合影響不大。
綜上所述,IgG1-M9作為ADC候選是不可行的,因其ADC產量低,及因過度疏水的CDR導致低DAR。相較之下,由篩選出具有結合及細胞毒性的特性的scFv (包含CHS5 IgG、CHS7 IgG、CHS8 IgG及ALA12 IgG)重建的IgG1可能為可行的ADC候選。相較於M9,該些IgG1與疏水性藥物vcMMAE鍵結展現較高的ADC產量及DAR (表2)。該些IgG1作為開發ADC之候選的可行性可歸因於其CDR-變異型序列編碼的親水性/帶電性胺基酸,以及與M9相比相對較高的RH-分數(表2)。
實施例4 由篩選出的scFv重建之IgG1作為PE38相關免疫毒素之標的模組的效力,及與vcMMAE偶聯的ADC的效力
PE38KDEL相關的免疫毒素,以及基於篩選出的M9 scFv CDR-變異性重建之IgG1的與vcMMAE偶聯之ADC於體外對N87細胞具有有效的細胞毒性(數據未顯示)。當可想見,IgG1-AL1-PE38KDEL的半最大抑制濃度(IC
50)聚集於最佳值(約0.1-0.2 nM),因為該些IgG是重建自經篩選出具有強效的scFv-AL1-PE38KDEL 細胞毒性的M9 scFv CDR-變異型(數據未顯示)。相似地,IgG1-vcMMAE的IC
50聚集在20-80 nM之間,表示使用相同IgG1也可有效作為vcMMAE相關的ADC於體外辨認N87細胞的標的模組。儘管如此,兩者的IC
50的關聯性並不顯著(R
2=0.056且P-值=0.13),表示IgG1-AL1-PE38KDEL及IgG1-vcMMAE的細胞毒性機制與數量無關,因此vcMMAE相關之ADC的效力只能由PE38KDEL相關的免疫毒素的細胞毒性之定性結果來推斷。儘管IgG1-vcMMAE的IC
50被預期與ADC的DAR相關,但兩者的相關性並不顯著(數據未顯示),表示ADC的IC
50與其他因素有關,例如IgG1-MSLN 交互作用親和性及DAR。
雖然IC
50的測量結果表示IgG1-AL1-PE38KDEL免疫毒素的有效性相較於IgG1-vcMMAE約提升1-2個數量級(數據未顯示),該些免疫毒素於動物疾病中的系統性毒性阻礙該些免疫毒素作為腫瘤治療劑的進一步發展。因此,於下文將4種IgG1-vcMMAE (亦即CHS5-vcMMAE、CHS7-vcMMAE、CHS8-vcMMAE及ALA12-vcMMAE)用於癌症治療的體內驗證。該些經篩選出的IgG1因具有高ADC功效、高ADC產量及DAR (數據未顯示),該些特性可能是因為IgG1之CDR的高親水性,如同該些IgG1的高RH-分數及較短的HIC滯留時間所反應出的結果(表2)。該些IgG1的高親和力及專一性是歸因於變異域的CDR中高保留的芳香殘基(數據未顯示)。
實施例5 M9-衍生的MSLN-陽性IgG1透過結合至細胞表面的MSLN傳遞細胞毒性有效負載的專一性
分析4種經篩選的IgG1-vcMMAE(亦即CHS5-vcMMAE、CHS7-vcMMAE、CHS8-vcMMAE及ALA12-vcMMAE)之細胞毒性專一性,並與正控制組SS1-vcMMAE比較,其中SS1-vcMMAE的抗-MSLN抗體已知會展現與MSLN的結合親和力及專一性。儘管有許多已知的抗-MSLN抗體,選擇SS1作為抗-MSLN抗體作為正控制組的原因在於,已有許多公開文獻紀載SS1。此外,SS1相關的治療已被登記於人類試驗中,並有公開資訊可製備SS1抗體(在相同框架中,在vcMMAE共軛方面與本研究的ADC進行並排比較)(數據未顯示)、測量細胞相關的細胞毒性(數據未顯示)、以及測量與vcMMAE相關之ADC的體內功效(第1A及第1B圖)及生物分布(第2A及第2B圖)。
選擇8個不會表現MSLN且源自不同器官的NCI-60細胞株,並驗證相比於4個MSLN-陽性控制組細胞該些細胞株不表現MSLN(數據未顯示)。在1-、2-和8-倍濃度的平均IC
50的ADC存在的情況下,測量5種IgG1-vcMMAE對有/無表現MSLN之細胞的細胞毒性(數據未顯示)。相較於ADC對正控制組的N87細胞的細胞毒性,該結果顯示在低於2-倍平均IC
50的ADC濃度下,並未在源自不同器官不表現MSLN之細胞上觀察到顯著的細胞毒性。雖然,有兩個NCI-60細胞株(M14及GR-OV1 (在較小程度上))在最高ADC濃度下產生細胞毒性(數據未顯示),然5種IgG1-vcMMAE在細胞毒性方面,對代表性的細胞株具有相似的專一性模式,暗示M41細胞可表現少量MSLN的可能性,只是其表現量低於西方墨點法的偵測極限(數據未顯示)。此結果表示,以該些IgG1-vcMMAE進行MSLN-陽性腫瘤的體內治療中不可能發生非專一性毒性,因為ADC測試的功效顯示ADC中抗體對細胞表面之MSLN的專一性標的具有明確關聯性。
實施例6 以抗-MSLN IgG1-vcMMAE對小鼠疾病模型中異種移植之腫瘤進行體內治療
在試驗的ADC組別中,以IgG1-vcMMAE (亦即CHS5-vcMMAE、CHS7-vcMMAE、CHS8-vcMMAE及ALA12-vcMMAE)治療小鼠體內的異種移植物N87 (人類胃)及Capan-2 (人類胰臟)腫瘤。於試驗中,SS1-vcMMAE作為正控制組、同型ADC及載體處理作為負控制組。選擇N87及Capan-2癌症模型是因為兩者皆為重要的人類癌症,其治療的選擇性都有限,且皆會表現MSLN於細胞表面(數據未顯示)。
第1A及第1B圖的數據分別繪示N87和Capan-2異種移植腫瘤於小鼠中的治療結果。兩項實驗均表明,ADC試驗組別中的4種抗-MSLN IgG1-vcMMAE,相較於正控制組的ADC (SS1-vcMMAE)對N87及Capan-2小鼠異種移植模型具有較佳的治療效果,且在幾種治療中幾乎完全根除異種移植腫瘤,明確的展現IgG1-vcMMAE於ADC試驗組別中相較於負控制組的處理具有較優異的治療功效(第1A及第1B圖)。
IgG1-vcMMAE於異種移植模型中的生物分布表示,控制組及ADC試驗組在上文所述的體內治療中絕大多數都集中於異種移植的腫瘤中。4種實驗的IgG1、正控制組及同型控制組的IgG1皆與螢光染劑偶聯,IgG1-染劑偶聯物產生的體內螢光影像顯示,在投予IgG1-染劑偶聯物之戲中移植腫瘤小鼠中的一天後,IgG1局部集中在N87及Capan-2異種移植腫瘤內(數據未顯示)。生物分布的離體定量測量指出所有標的N87及Capan-2腫瘤的IgG1,儘管有少量不顯著的IgG1被發現分布於小鼠疾病模型的肺部,但該些IgG1局部濃度高且對所有器官的脫靶傾向低(第2A及第2B圖)。IgG1的腫瘤重度生物分佈(第2A及第2B圖)與IgG1的MSLN專一性標的能力一致。以該些IgG1-vcMMAE治療的N87及Capan-2異種移植小鼠的血清生化參數進一步指出,以該些IgG1-vcMMAE進行體內治療伴隨著無法偵測的脫靶毒性(表3及表4)。
表3 抗-MSLN IgG1-vc-MMAE對N87 NOD/SCID小鼠中血清生化參數的影響
實驗終點表示6隻小鼠的平均值± SD。丙胺酸轉胺酶(alanine aminotransferase,ALT)、鹼性磷酸酶(alkaline phosphatase,ALP)、血尿素氮(blood urea nitrogen,BUN)、肌酸酐(creatinine,CRE)。
N87 | ALT(U/L) | ALP(U/L) | BUN(mg/dL) | CRE(mg/dL) | ALT/ALP |
PBS | 38.17± 9.21 | 143.67 ± 37.73 | 26.18 ± 1.11 | 0.58 ± 0.16 | 0.27 |
同型控制組-vcMMAE | 32.67 ± 19.05 | 99.00-± 22.18 | 21.15-± 2.31 | 0.77-± 0.06 | 0.33 |
SS1-vcMMAE | 38.50 ± 45.18 | 109.17 ± 23.08 | 21.02 ± 1.45 | 0.57 ± 0.26 | 0.35 |
CHS5-vcMMAE | 20.67 ± 3.09 | 104.67 ± 14.21 | 20.88 ± 1.83 | 0.57 ± 0.16 | 0.20 |
CHS7-vcMMAE | 20.67 ± 2.56 | 99.83 ± 8.55 | 21.32 ± 1.68 | 0.79 ± 0.07 | 0.21 |
CHS8-vcMMAE | 22.83 ± 5.84 | 105.33 ± 13.61 | 24.55 ± 1.66 | 0.48 ± 0.11 | 0.22 |
ALA12-vcMMAE | 21.17 ± 4.37 | 94.50 ± 8.52 | 21.57 ± 1.30 | 0.58 ± 0.16 | 0.22 |
表4 抗-MSLN IgG1-vcMMAE對Capan-2 NOD/SCID小鼠中血清生化參數的影響
實驗終點表示6隻小鼠的平均值± SD。丙胺酸轉胺酶(alanine aminotransferase,ALT)、鹼性磷酸酶(alkaline phosphatase,ALP)、血尿素氮(blood urea nitrogen,BUN)、肌酸酐(creatinine,CRE)。
Capan2 | ALT (U/L) | ALP (U/L) | BUN (mg/dL) | CRE (mg/dL) | ALT/ALP |
PBS | 16.33 ± 1.80 | 75.83 ± 17.32 | 25.13 ± 4.32 | 0.79 ± 0.12 | 0.22 |
同型控制組-vcMMAE | 19.33 ± 8.42 | 88.17 ± 9.99 | 20.75 ± 1.30 | 0.65 ± 0.23 | 0.22 |
SS1-vcMMAE | 26.67 ± 13.91 | 102.50 ± 25.17 | 22.53 ± 11.65 | 0.82 ± 0.29 | 0.26 |
CHS5-vcMMAE | 18.83 ± 1.67 | 98.67 ± 7.87 | 21.88 ± 0.75 | 0.77 ± 0.09 | 0.19 |
CHS7-vcMMAE | 16.67 ± 2.36 | 107.17 ± 23.13 | 21.82 ± 2.49 | 0.64 ± 0.06 | 0.16 |
CHS8-vcMMAE | 16.00 ± 1.00 | 87.00 ± 9.18 | 22.30 ± 1.33 | 0.64 ± 0.14 | 0.18 |
ALA12-vcMMAE | 18.50 ± 2.29 | 92.00 ± 19.51 | 21.88 ± 2.05 | 0.62 ± 0.14 | 0.18 |
在N87疾病模型中,以正控制組及某些ADC試驗組中的IgG1-vcMMAE進行部分腫瘤根除的治療效果較差,可能是因為在ADC治療過程中N87異種移植小鼠中的極端的腫瘤尺寸所導致。與Capan-2腫瘤相對較低侵襲性的生長速度(第1B及第2B圖)相比,N87異種移植腫瘤在小鼠中的高度侵襲性生長也可以解釋N87腫瘤中同型控制組IgG1的吸收(第2A圖),解釋以同型控制組ADC治療N87腫瘤疾病模型的部分治療效果(第1A圖)。
總結上述,ADC試驗組中的4種IgG1-vcMMAE為有效的ADC治療,且於治療小鼠中N87及Capan-2異種移植腫瘤時沒有可偵測到的非專一性毒性。此外,CHS5-vcMMAE於兩種腫瘤疾病模型中具有優異的腫瘤根除功效,因此以CHS5-vcMMAE進行體內治療特別令人感興趣。儘管IgG1-CHS5對MSLN的親和力並非所有ADC試驗組的IgG1中最高的,且IgG1-CHS5的DAR (2.56)為所有用於體內治療的ADC中最低的,然而其親水性、ADC產量、DAR、IgG1-CHS5的體外細胞毒性及細胞表面MSLN-標的專一性皆為ADC試驗組中所有IgG1中最優異的。這些結果突顯特徵收集在確定候選ADC於導致腫瘤根除的體內治療中的功效和專一性時的重要性。
應當理解的是,前述實施方式的描述僅是以實施例的方式給出,且本發明所屬技術領域中具有通常知識者可進行各種修改。以上說明書、實施例及實驗結果提供本發明之例示性實施方式之結構與用途的完整描述。雖然上文實施方式中揭露了本發明的具體實施例,然其並非用以限定本發明,本發明所屬技術領域中具有通常知識者,在不悖離本發明之原理與精神的情形下,當可對其進行各種更動與修飾,因此本發明之保護範圍以附隨申請專利範圍界定者為準。
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在參閱以下的詳細說明及隨附圖式後,本揭示內容當更加明顯易懂,其中:
第1A及1B圖是依據本揭示內容一實施例所繪示的分析結果,分別闡述以抗-MSLN之IgG1-vcMMAE來治療N87及Capan-2異種移植小鼠模型。利用四種ADC試驗組的IgG1-vcMMAE (包含CHS5-vcMMAE、CHS7-vcMMAE、CHS8-vcMMAE以及ALA12-vcMMAE)於活體內治療N87 (第1A圖)及Capan-2 (第1B圖)的異種移植小鼠模型,將治療結果與ADC正控制組(SS1-vcMMAE)、同型ADC控制組(S40-vcMMAE)及空白對照組相比。以雙尾的學生t-檢定的P-值表示統計的顯著性(*p < 0.05)。
第2A及2B圖是依據本揭示內容一實施例所繪示的分析結果,分別闡述N87 (第2A圖)及Capan-2 (第2B圖)異種移植小鼠模型中與螢光染劑鍵結的抗-MSLN之IgG1的生物分佈(bio-distribution)。以各實驗組中三隻小鼠來計算生物分佈的平均值及標準差。
序列表 <![CDATA[<110> 中央研究院]]> <![CDATA[<120> 一種用以篩選對間皮素具有專一性之抗體片段的噬菌體表現單鏈變異片段抗體庫]]> <![CDATA[<130> P4191-PCT]]> <![CDATA[<150> US63208496]]> <![CDATA[<151> 2021-06-08]]> <![CDATA[<160> 46]]> <![CDATA[<170> BiSSAP 1.3]]> <![CDATA[<210> 1]]> <![CDATA[<211> 63]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CDR-L1引子]]> <![CDATA[<220> ]]> <![CDATA[<221> 突變]]> <![CDATA[<222> 31,32,34,35,37,38]]> <![CDATA[<223> N是A、T、C或G]]> <![CDATA[<400> 1]]> accattacct gccgtgcgag ccaggatgtt nnknnknnkg tcgcatggta tcagcagaaa 60 cca 63 <![CDATA[<210> 2]]> <![CDATA[<211> 69]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CDR-L2引子]]> <![CDATA[<220> ]]> <![CDATA[<221> 突變]]> <![CDATA[<222> 25,26,28,29,31,32,34,35,37,38]]> <![CDATA[<223> N是A、T、C或G]]> <![CDATA[<400> 2]]> ggcaaagcgc cgaaacttct gatannknnk nnknnknnkc tgtatagcgg cgtgccgtcg 60 cgtttttcg 69 <![CDATA[<210> 3]]> <![CDATA[<211> 69]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> 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6]]> <![CDATA[<211> 66]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CDR-H3引子]]> <![CDATA[<220> ]]> <![CDATA[<221> 突變]]> <![CDATA[<222> 25,26,28,29,31,32,34,35,37,38]]> <![CDATA[<223> N是A、T、C或G]]> <![CDATA[<400> 6]]> acagcggtgt attattgcgc gcgtnnknnk nnknnknnkg attattgggg gcagggcacc 60 cttgtt 66 <![CDATA[<210> 7]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-L1]]> <![CDATA[<400> 7]]> Arg Ala Ser Gln Asp Val Lys Glu Gly Val Ala 1 5 10 <![CDATA[<210> 8]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-L2]]> <![CDATA[<400> 8]]> Asp Gln Ser His Arg Leu Tyr Ser 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-L3]]> <![CDATA[<400> 9]]> Gln Gln Tyr Tyr Ala Trp Pro Ser Thr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-H1]]> <![CDATA[<400> 10]]> Ala Ala Ser Gly Phe Thr Ile Thr Asp Arg Thr Ile His 1 5 10 <![CDATA[<210> 11]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-H2]]> <![CDATA[<400> 11]]> Ser Ile Phe Pro Thr Lys Gly Val Thr Thr 1 5 10 <![CDATA[<210> 12]]> <![CDATA[<211> 9]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_CDR-H3]]> <![CDATA[<400> 12]]> Ala Arg Gly Arg Tyr Trp Met Asp Tyr 1 5 <![CDATA[<210> 13]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_CDR-L1]]> <![CDATA[<400> 13]]> Arg Ala Ser Gln Asp Val Glu Asp Gly Val Ala 1 5 10 <![CDATA[<210> 14]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_CDR-L2]]> <![CDATA[<400> 14]]> Gly Ile Lys Asp Leu Leu Tyr Ser 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_CDR-L3]]> <![CDATA[<400> 15]]> Gln Gln Tyr Tyr Arg Trp Pro Ser Thr 1 5 <![CDATA[<210> 16]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_CDR-H1]]> <![CDATA[<400> 16]]> Ala Ala Ser Gly Phe Thr Ile Asp Lys Glu Ala Ile His 1 5 10 <![CDATA[<210> 17]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_CDR-H2]]> <![CDATA[<400> 17]]> Ser Ile Tyr Pro His Ser Gly Phe Thr Leu 1 5 10 <![CDATA[<210> 18]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_CDR-L2]]> <![CDATA[<400> 18]]> Asp Glu Arg Glu Arg Leu Tyr Ser 1 5 <![CDATA[<210> 19]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_CDR-L3]]> <![CDATA[<400> 19]]> Gln Gln Tyr Asn Thr Trp Pro Ala Thr 1 5 <![CDATA[<210> 20]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_CDR-H1]]> <![CDATA[<400> 20]]> Ala Ala Ser Gly Phe Thr Ile Ser Lys Ala Ser Ile His 1 5 10 <![CDATA[<210> 21]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_CDR-H2]]> <![CDATA[<400> 21]]> Ser Ile Trp Pro Thr Lys Gly Phe Thr Thr 1 5 10 <![CDATA[<210> 22]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_CDR-H3]]> <![CDATA[<400> 22]]> Ala Arg Gly Arg Tyr Trp Leu Asp Tyr 1 5 <![CDATA[<210> 23]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_CDR-L1]]> <![CDATA[<400> 23]]> Arg Ala Ser Gln Asp Val Arg Asp Gly Val Ala 1 5 10 <![CDATA[<210> 24]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_CDR-L2]]> <![CDATA[<400> 24]]> Asp Gln Met Val Arg Leu Tyr Ser 1 5 <![CDATA[<210> 25]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_CDR-L3]]> <![CDATA[<400> 25]]> Gln Gln Tyr Phe Asn Trp Pro Val Thr 1 5 <![CDATA[<210> 26]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_CDR-H1]]> <![CDATA[<400> 26]]> Ala Ala Ser Gly Phe Thr Ile Gly Asn Trp Thr Ile His 1 5 10 <![CDATA[<210> 27]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_CDR-H2]]> <![CDATA[<400> 27]]> Leu Ile Trp Pro Glu Ser Gly Ala Thr Leu 1 5 10 <![CDATA[<210> 28]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_VL域]]> <![CDATA[<400> 28]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Lys Glu Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Asp Gln Ser His Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala Trp Pro Ser 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 29]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS5_VL域]]> <![CDATA[<400> 29]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Thr Asp Arg 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Phe Pro Thr Lys Gly Val Thr Thr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Tyr Trp Met Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 30]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_VL域]]> <![CDATA[<400> 30]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Glu Asp Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Gly Ile Lys Asp Leu Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Arg Trp Pro Ser 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 31]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS7_VH域]]> <![CDATA[<400> 31]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Asp Lys Glu 20 25 30 Ala Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Tyr Pro His Ser Gly Phe Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Tyr Trp Met Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 32]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_VL域]]> <![CDATA[<400> 32]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Lys Glu Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Asp Glu Arg Glu Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Trp Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 33]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_CHS8_VH域]]> <![CDATA[<400> 33]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Lys Ala 20 25 30 Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Trp Pro Thr Lys Gly Phe Thr Thr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Tyr Trp Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 34]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_VL域]]> <![CDATA[<400> 34]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Arg Asp Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Asp Gln Met Val Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Phe Asn Trp Pro Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 35]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ALA12_VH域]]> <![CDATA[<400> 35]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Gly Asn Trp 20 25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile Trp Pro Glu Ser Gly Ala Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Tyr Trp Met Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 36]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_ER滯留胜肽]]> <![CDATA[<400> ]]>36 Lys Asp Glu Leu 1 <![CDATA[<210> 37]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_first polypeptide]]> <![CDATA[<400> 37]]> Ala Ser Ala Ala Gly Gly Ser Gly Thr 1 5 <![CDATA[<210> 38]]> <![CDATA[<211> 138]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_適體]]> <![CDATA[<400> 38]]> Tyr Asn Lys Asp Gln Gln Ser Ala Phe Tyr Glu Ile Leu Asn Met Pro 1 5 10 15 Asn Leu Asn Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp 20 25 30 Asp Pro Ser Gln Ser Thr Asn Val Leu Gly Glu Ala Lys Lys Leu Asn 35 40 45 Glu Ser Gln Ala Pro Lys Ala Asp Asn Gly Gly Gly Ser Gly Gly Gly 50 55 60 Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Ser Glu Val Thr Ile 65 70 75 80 Lys Val Asn Leu Ile Phe Ala Asp Gly Lys Ile Gln Thr Ala Glu Phe 85 90 95 Lys Gly Thr Phe Glu Glu Ala Thr Ala Glu Ala Tyr Arg Tyr Ala Ala 100 105 110 Leu Leu Ala Lys Val Asn Gly Glu Tyr Thr Ala Asp Leu Glu Asp Gly 115 120 125 Gly Asn His Met Asn Ile Lys Phe Ala Gly 130 135 <![CDATA[<210> 39]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-L1]]> <![CDATA[<400> 39]]> Arg Ala Ser Gln Asp Val Asn Asp Gly Val Ala 1 5 10 <![CDATA[<210> 40]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-L2]]> <![CDATA[<400> 40]]> Ser Gly Ser Pro Trp Leu Tyr Ser 1 5 <![CDATA[<210> 41]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-L3]]> <![CDATA[<400> 41]]> Gln Gln Tyr Phe Asn Trp Pro Ile Thr 1 5 <![CDATA[<210> 42]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-H1]]> <![CDATA[<400> 42]]> Ala Ala Ser Gly Phe Thr Ile Asp Asn Tyr Gly Ile His 1 5 10 <![CDATA[<210> 43]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-H2]]> <![CDATA[<400> 43]]> Trp Ile Trp Pro Tyr Gly Gly Ser Thr Tyr 1 5 10 <![CDATA[<210> 44]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_M9_CDR-H3]]> <![CDATA[<400> 44]]> Ala Arg Gly Tyr Tyr Trp Tyr Asp Tyr 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_類型I胺基酸序列]]> <![CDATA[<400> 45]]> Ser Thr Asn Gln Gly 1 5 <![CDATA[<210> 46]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> 合成_類型II胺基酸序列]]> <![CDATA[<400> 46]]> Lys Arg His Asp Glu 1 5
Claims (22)
- 一種由噬菌體表現之單鏈變異片段(single-chain variable fragment, scFv)抗體庫,包含複數個由噬菌體表現的scFv,其中該些由噬菌體表現之scFv各包含一第一輕鏈互補決定區(first light chain complementarity determining region, CDR-L1)、一第二輕鏈互補決定區(second light chain CDR, CDR-L2)、一第三輕鏈互補決定區(third light chain CDR, CDR-L3)、一第一重鏈互補決定區(first heavy chain CDR, CDR-H1)、一第二重鏈互補決定區(second heavy chain CDR, CDR-H2)以及一第三重鏈互補決定區(third heavy chain CDR, CDR-H3),其中 該CDR-L1是由一包含序列編號:1之核苷酸序列的第一編碼序列編碼而成,該CDR-L2是由一包含序列編號:2之核苷酸序列的第二編碼序列編碼而成,該CDR-L3是由一包含序列編號:3之核苷酸序列的第三編碼序列編碼而成,該CDR-H1是由一包含序列編號:4之核苷酸序列的第四編碼序列編碼而成,該CDR-H2是由一包含序列編號:5之核苷酸序列的第五編碼序列編碼而成,以及該CDR-H3是由一包含序列編號:6之核苷酸序列的第六編碼序列編碼而成。
- 如請求項1所述之由噬菌體表現之scFv抗體庫,其中該噬菌體為一M13噬菌體或一T7噬菌體。
- 如請求項1所述之由噬菌體表現之scFv抗體庫,其中該由噬菌體表現之scFv抗體庫包含一第一、一第二、一第三及一第四由噬菌體表現的scFv,其中 該第一由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:7、8、9、10、11及12的胺基酸序列; 該第二由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:13、14、15、16、17及12的胺基酸序列; 該第三由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:7、18、19、20、21及22的胺基酸序列;以及 該第四由噬菌體表現之scFv的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2及CDR-H3分別包含序列編號:23、24、25、26、27及12的胺基酸序列。
- 一種重組抗體,包含一輕鏈變異(light chain variable、VL)域及一重鏈變異(heavy chain variable、VH)域,其中 該VL域包含序列編號:7-9的胺基酸序列,且該VH域包含序列編號:10-12的胺基酸序列; 該VL域包含序列編號:13-15的胺基酸序列,且該VH域包含序列編號:16、17及12的胺基酸序列; 該VL域包含序列編號:7、18及19的胺基酸序列,且該VH域包含序列編號:20-22的胺基酸序列;或是 該VL域包含序列編號:23-25的胺基酸序列,且該VH域包含序列編號:26、27及12的胺基酸序列。
- 如請求項4所述之重組抗體,其中 該VL域包含一與序列編號:28具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:29具有至少85%之序列相似度的胺基酸序列; 該VL域包含一與序列編號:30具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:31具有至少85%之序列相似度的胺基酸序列; 該VL域包含一與序列編號:32具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:33具有至少85%之序列相似度的胺基酸序列;或是 該VL域包含一與序列編號:34具有至少85%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:35具有至少85%之序列相似度的胺基酸序列。
- 如請求項5所述之重組抗體,其中 該VL域包含一與序列編號:28具有100%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:29具有100%之序列相似度的胺基酸序列; 該VL域包含一與序列編號:30具有100%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:31具有100%之序列相似度的胺基酸序列; 該VL域包含一與序列編號:32具有100%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:33具有100%之序列相似度的胺基酸序列;或是 該VL域包含一與序列編號:34具有100%之序列相似度的胺基酸序列,且該VH域包含一與序列編號:35具有100%之序列相似度的胺基酸序列。
- 一種免疫偶聯物,包含如請求項4所述之重組抗體、一功能性模體(motif)以及一連接該重組抗體及該功能性模體的連接子。
- 如請求項7所述之免疫偶聯物,其中該功能性模體包含一免疫毒素或一細胞毒性藥物。
- 如請求項8所述之免疫偶聯物,其中該免疫毒素為一外毒素。
- 如請求項9所述之免疫偶聯物,其中該外毒素為綠膿桿菌外毒素( Pseudomonas Exotoxin, PE) A或其衍生物。
- 如請求項9所述之免疫偶聯物,其中該功能性模體更包含一與該外毒素連接的內質網(endoplasmic reticulum, ER)滯留胜肽。
- 如請求項11所述之免疫偶聯物,其中該ER滯留胜肽包含序列編號:36之胺基酸序列。
- 如請求項8所述之免疫偶聯物,其中該細胞毒性藥物為澳瑞他汀(auristatin)或其衍生物。
- 如請求項13所述之免疫偶聯物,其中該細胞毒性藥物為單甲基澳瑞他汀E。
- 如請求項7所述之免疫偶聯物,其中該連接子為 一纈胺酸-瓜胺酸雙胜肽(valine-citrulline dipeptide); 一包含序列編號:37之胺基酸序列的第一多肽;或是 一適體(adaptor),包含至少一AL模組,其中該AL模組包含一位於N-端的蛋白A片段,一位於C-端的蛋白L片段,以及一連接該蛋白A片段及該蛋白L片段的第二多肽。
- 如請求項15所述之免疫偶聯物,其中該適體包含序列編號:38之胺基酸序列。
- 一種藥學組合物,包含如請求項7所述之免疫偶聯物以及一藥學上可接受之賦形劑。
- 一種如請求項7所述之免疫偶聯物或如請求項17所述之藥學組合物於製備一用以治療一個體之癌症之藥物的用途。
- 如請求項18所述之用途,其中該癌症具有MSLN表現於其上。
- 如請求項19所述之用途,其中該癌症為胃癌、肺癌、膀胱癌、乳癌、胰臟癌、腎臟癌、大腸直腸癌、子宮頸癌、卵巢癌、腦癌、前列腺癌、肝細胞癌、黑色素瘤、食道癌、多發性骨髓瘤或是頭頸部鱗狀細胞癌。
- 如請求項20所述之用途,其中該癌症為胃癌或胰臟癌。
- 如請求項18所述之用途,其中該個體為人類。
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